Genetic Variant ZMYM3:p.Val1317Met (chrX-71241080-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_201599.3(ZMYM3):c.3949G>A(p.Val1317Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000108 in 1,207,691 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000010 ( 0 hom. 2 hem. )

Consequence

ZMYM3
NM_201599.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.893

Variant links:

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]

ZMYM3 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.31651202).

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZMYM3	NM_201599.3 link	c.3949G>A	p.Val1317Met	missense_variant	Exon 25 of 25	ENST00000314425.9	NP_963893.1	Q14202-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZMYM3	ENST00000314425.9 link	c.3949G>A	p.Val1317Met	missense_variant	Exon 25 of 25	1	NM_201599.3	ENSP00000322845.5		Q14202-1

Frequencies

GnomAD3 genomes

AF:

0.0000181

AC:

AN:

110740

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32934

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000378

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000100

AC:

AN:

1096951

Hom.:

Cov.:

AF XY:

0.00000552

AC XY:

AN XY:

362335

show subpopulations

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:

0.0000131

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000181

AC:

AN:

110740

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32934

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000378

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jan 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3949G>A (p.V1317M) alteration is located in exon 25 (coding exon 24) of the ZMYM3 gene. This alteration results from a G to A substitution at nucleotide position 3949, causing the valine (V) at amino acid position 1317 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;.;T;T

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.32

T;T;T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

1.5

L;.;.;.

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.9

N;N;N;N

REVEL

Benign

0.037

Sift

Benign

0.085

T;T;T;T

Sift4G

Uncertain

0.022

D;D;D;D

Polyphen

0.24

B;B;.;.

Vest4

0.32

MutPred

0.31

Loss of phosphorylation at Y1319 (P = 0.0759);.;.;.;

MVP

0.36

ClinPred

0.74

GERP RS

4.6

Varity_R

0.16

gMVP

0.86

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over