Human Gene Module / Chromosome 13 / ZMYM2

ZMYM2zinc finger MYM-type containing 2

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
6 / 10
Rare Variants / Common Variants
44 / 0
Aliases
ZMYM2, FIM,  MYM,  RAMP,  SCLL,  ZNF198
Associated Syndromes
-
Chromosome Band
13q12.11
Associated Disorders
DD/NDD, ID, ASD, EPS
Relevance to Autism

Heterozygous mutations in ZMYM2 were recently observed in 19 individuals presenting with a multisystem syndrome characterized by congenital anomalies of the kidney and urinary tract (CAKUT), cardiac defects, dysmorphic facial features, and/or neurological features, including 4 individuals with autism spectrum disorder and 2 others with stereotypy (Connaughton et al., 2020). Two de novo variants in ZMYM2 (one frameshift variant, one missense variant with a CADD score of 29.9) were reported in ASD probands from the SPARK cohort in Wang et al., 2020, while single-molecular molecular inversion probe (smMIP) sequencing of 125 genes in over 16,000 cases with neurodevelopmental disorders in the same report identified a number of ASD-associated likely gene-disruptive and missense variants with CADD scores 30, including a de novo frameshift variant in a proband from the Italian Autism Network (ITAN) cohort, in ZMYM2. A maternally-inherited likely gene-disruptive variant in ZMYM2 was transmitted to two of three ASD-affected siblings in a multiplex family from the iHART cohort in Russo et al., 2019.

Molecular Function

The protein encoded by this gene is a zinc finger protein that may act as a transcription factor. The encoded protein may be part of a BHC histone deacetylase complex.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ZMYM2 (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Prevalence and architecture of de novo mutations in developmental disorders et al. (2017) No -
2 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
3 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
4 Primary Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations Connaughton DM et al. (2020) No ASD, DD, ID, stereotypy, epilepsy/seizures
5 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
6 Recent recommendation - Mojarad BA et al. (2021) No -
7 Support - Singh T et al. (2022) No -
8 Support - Zhou X et al. (2022) Yes -
9 Support - Yuan B et al. (2023) Yes -
10 Support - Wang J et al. (2023) Yes -
Rare Variants   (44)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1105C>T p.Pro369Ser stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.2083A>T p.Asn695Tyr stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.190G>A p.Glu64Lys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1960G>T p.Glu654Ter stop_gained Unknown - - 33526774 Mojarad BA et al. (2021)
c.2687C>T p.Pro896Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3635C>T p.Pro1212Leu missense_variant De novo - - 33004838 Wang T et al. (2020)
c.3758C>T p.Thr1253Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4069C>T p.Arg1357Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.633del p.Leu212Ter frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.701del p.Ser234Ter frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.977dup p.Val327SerfsTer2 frameshift_variant De novo - - 28135719 et al. (2017)
c.428C>T p.Pro143Leu stop_gained Unknown - - 32891193 Connaughton DM et al. (2020)
c.3648G>C p.Leu1216%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.3118C>T p.Arg1040Ter stop_gained De novo - Simplex 37393044 Wang J et al. (2023)
c.1192C>T p.Gln398Ter stop_gained De novo - - 32891193 Connaughton DM et al. (2020)
c.1424C>T p.Pro475Leu stop_gained De novo - - 32891193 Connaughton DM et al. (2020)
c.1424C>T p.Pro475Leu stop_gained Unknown - - 32891193 Connaughton DM et al. (2020)
c.2338C>T p.Arg780Ter stop_gained De novo - - 32891193 Connaughton DM et al. (2020)
c.2253dup p.Glu752Ter frameshift_variant Unknown - - 33526774 Mojarad BA et al. (2021)
c.2899dup p.Thr967AsnfsTer9 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.2584dup p.Tyr862LeufsTer3 frameshift_variant De novo - - 36881370 Yuan B et al. (2023)
c.3301+3_3301+6del - splice_site_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1044del p.Gly349AspfsTer32 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.1474del p.Arg492AspfsTer14 frameshift_variant De novo - - 33004838 Wang T et al. (2020)
c.2175del p.Thr726LeufsTer21 frameshift_variant De novo - - 33004838 Wang T et al. (2020)
c.2827del p.Ser943GlnfsTer11 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.763_766del p.Gly255Ter frameshift_variant Unknown - - 33526774 Mojarad BA et al. (2021)
c.3369dup p.His1124SerfsTer5 splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.1925G>C p.Cys642Ser missense_variant Unknown Not maternal - 30564305 Guo H , et al. (2018)
c.2165T>A p.Leu722Ter stop_gained Familial Maternal - 32891193 Connaughton DM et al. (2020)
c.2134_2135del p.Tyr712GlnfsTer23 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.2624_2669del p.Asp875ValfsTer48 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.3370_3373del p.His1124LeufsTer51 splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.1174dup p.Asp392GlyfsTer4 frameshift_variant De novo - - 32891193 Connaughton DM et al. (2020)
c.2982dup p.Met995HisfsTer3 frameshift_variant De novo - - 32891193 Connaughton DM et al. (2020)
c.3301del p.Ser1101LeufsTer4 splice_site_variant Unknown - Simplex 33004838 Wang T et al. (2020)
c.3922G>T p.Glu1308Ter stop_gained Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.1413del p.Glu472SerfsTer14 frameshift_variant Unknown - - 32891193 Connaughton DM et al. (2020)
c.573_574dup p.Thr192LysfsTer4 frameshift_variant De novo - - 32891193 Connaughton DM et al. (2020)
c.3052G>A p.Asp1018Asn stop_gained Familial Maternal Simplex 32891193 Connaughton DM et al. (2020)
c.2494-1G>A - splice_site_variant Familial Maternal Multiplex 32891193 Connaughton DM et al. (2020)
c.1429_1433del p.Lys477CysfsTer4 frameshift_variant De novo - - 32891193 Connaughton DM et al. (2020)
c.2240_2243del p.Arg747IlefsTer40 frameshift_variant De novo - Multiplex 32891193 Connaughton DM et al. (2020)
c.2936_2937dup p.Gly980LeufsTer6 frameshift_variant Unknown Not paternal - 32891193 Connaughton DM et al. (2020)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

Score Delta: Score remained at 2S

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2022
icon
2S

Increased from to 2S

Krishnan Probability Score

Score 0.50454596959126

Ranking 1923/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.97445995590236

Ranking 2264/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.93762376216829

Ranking 13587/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.39001415574224

Ranking 1563/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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