X-71241000-C-A

Position:

• chrX-71241000-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PS1 PM2 BP4_Moderate

The ENST00000314425.9(ZMYM3):​c.4029G>T​(p.Met1343Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin Lovd.

• Frequency: Genomes: not found (cov: 22)
• Consequence: ZMYM3 ENST00000314425.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.52

Genes affected

ZMYM3 (HGNC:13054): (zinc finger MYM-type containing 3) This gene is located on the X chromosome and is subject to X inactivation. It is highly conserved in vertebrates and most abundantly expressed in the brain. The encoded protein is a component of histone deacetylase-containing multiprotein complexes that function through modifying chromatin structure to keep genes silent. A chromosomal translocation (X;13) involving this gene is associated with X-linked cognitive disability. Several alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PS1: Transcript ENST00000314425.9 (ZMYM3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12351808).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZMYM3	NM_201599.3	c.4029G>T	p.Met1343Ile	missense_variant	25/25	ENST00000314425.9	NP_963893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZMYM3	ENST00000314425.9	c.4029G>T	p.Met1343Ile	missense_variant	25/25	1	NM_201599.3	ENSP00000322845	P4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual developmental disorder, X-linked 112 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Aug 23, 2024

A hemizygous missense variation in exon 25 of the ZMYM3 gene that results in the amino acid substitution of Isoleucine for Methionine at codon 1343 was detected. The observed variant c.4029G>T (p.Met1343lle) has not been reported in the 1000 genomes, gnomAD (v3.1), gnomAD (v2.1), topmed and our internal databases. The in silico prediction of the variant is damaging by SIFT. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.061	T;.;T;T
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.85	D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;.;.;.
MutationTaster	Benign	0.82	N;N;N;N;N
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.53	N;N;N;N
REVEL	Benign	0.066
Sift	Benign	0.41	T;T;T;T
Sift4G	Benign	0.10	T;T;D;T
Polyphen		0.027	B;B;.;.
Vest4		0.19
MutPred		0.37		Gain of catalytic residue at M1343 (P = 0.0026);.;.;.;
MVP		0.37
ClinPred		0.64	D
GERP RS		4.3
Varity_R		0.31
gMVP		0.89

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-70460850;