10-180049-A-G

Position:

• chr10-180049-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4 BS1_Supporting BS2

The NM_001370100.5(ZMYND11):​c.37A>G​(p.Lys13Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,461,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: ZMYND11 NM_001370100.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 8.79

Genes affected

ZMYND11 (HGNC:16966): (zinc finger MYND-type containing 11) The protein encoded by this gene was first identified by its ability to bind the adenovirus E1A protein. The protein localizes to the nucleus. It functions as a transcriptional repressor, and expression of E1A inhibits this repression. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ZMYND11. . Gene score misZ: 3.7109 (greater than the threshold 3.09). Trascript score misZ: 4.725 (greater than threshold 3.09). The gene has 14 curated pathogenic missense variants (we use a threshold of 10). The gene has 21 curated benign missense variants. GenCC has associacion of the gene with intellectual disability, autosomal dominant 40, syndromic complex neurodevelopmental disorder, autosomal dominant non-syndromic intellectual disability, intellectual disability, autosomal dominant 30.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2937649).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000205 (30/1461522) while in subpopulation NFE AF= 0.0000261 (29/1111788). AF 95% confidence interval is 0.0000183. There are 0 homozygotes in gnomad4_exome. There are 13 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZMYND11	NM_001370100.5	c.37A>G	p.Lys13Glu	missense_variant	2/15	ENST00000381604.9	NP_001357029.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZMYND11	ENST00000381604.9	c.37A>G	p.Lys13Glu	missense_variant	2/15	5	NM_001370100.5	ENSP00000371017.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248716 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135152

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461522 Hom.: 0 Cov.: 30 AF XY: 0.0000179 AC XY: 13 AN XY: 727058

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00000831 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 11, 2024

Variant summary: ZMYND11 c.37A>G (p.Lys13Glu) results in a conservative amino acid change located in the SAM domain-containing protein 1-like, WH domain (IPR048589) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 248716 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.37A>G in individuals affected with Intellectual Disability, Autosomal Dominant 30 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1064553). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Intellectual disability, autosomal dominant 30 Uncertain:1

Uncertain significance, criteria provided, single submitter

research

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Jan 01, 2020

ZMYND11 c.37A>G (p.Lys13Glu) is a missense variant that changes a single amino acid from a lysine to a glutamic acid. This variant has been rarely observed in human population databases (< 1 in 20,000 alleles). It has not been reported previously in the clinical literature and is of uncertain clinical significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 13, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1064553). This variant has not been reported in the literature in individuals affected with ZMYND11-related conditions. This variant is present in population databases (rs759490914, gnomAD 0.0009%). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 13 of the ZMYND11 protein (p.Lys13Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.021	T;T;.;T;.;T;.;.;T;.;.;.
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;.;D;D;D;D;D;D;D;.;D;D
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.29	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.4	.;L;L;.;L;L;.;L;.;L;.;L
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.2	N;N;N;.;N;N;N;.;N;.;N;N
REVEL	Benign	0.20
Sift	Benign	0.084	T;T;T;.;T;T;T;.;T;.;T;T
Sift4G	Benign	0.078	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0060	.;.;.;B;.;.;.;.;B;.;.;.
Vest4		0.56, 0.65, 0.66, 0.66, 0.56, 0.65, 0.66, 0.64, 0.64, 0.69
MutPred		0.32		Loss of MoRF binding (P = 0.0052);Loss of MoRF binding (P = 0.0052);Loss of MoRF binding (P = 0.0052);Loss of MoRF binding (P = 0.0052);Loss of MoRF binding (P = 0.0052);Loss of MoRF binding (P = 0.0052);Loss of MoRF binding (P = 0.0052);Loss of MoRF binding (P = 0.0052);Loss of MoRF binding (P = 0.0052);Loss of MoRF binding (P = 0.0052);Loss of MoRF binding (P = 0.0052);Loss of MoRF binding (P = 0.0052);
MVP		0.26
MPC		2.1
ClinPred		0.46	T
GERP RS		6.0
Varity_R		0.16
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs759490914; hg19: chr10-225989;