15-57639459-G-T

Position:

chr15-57639459-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001018100.5(MYZAP):c.1033G>T(p.Ala345Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000991 in 1,613,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

MYZAP
NM_001018100.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.58

Variant links:

Genes affected

MYZAP (HGNC:43444): (myocardial zonula adherens protein) This gene encodes a protein that is abundantly expressed in cardiac tissue. The encoded protein localizes to intercalated discs in cardiomyocytes and functions as an activator of Rho-dependent serum-response factor signaling. Alternative splicing results in multiple transcript variants. Readthrough transcription also exists between this gene and the neighboring downstream gene POLR2M (polymerase (RNA) II (DNA directed) polypeptide M) and is represented with GeneID: 145781. [provided by RefSeq, Mar 2014]

MYZAP links:

GCOM1 (HGNC:26424): (GCOM1, MYZAP-POLR2M combined locus) This locus represents naturally occurring readthrough transcription between the neighboring MYZAP (myocardial zonula adherens protein) and POLR2M (polymerase (RNA) II (DNA directed) polypeptide M) genes on chromosome 15. Alternative splicing results in multiple readthrough transcript variants. Readthrough variants may encode proteins that share sequence identity with the upstream gene product or with both the upstream and downstream gene products. Some readthrough transcript variants are also expected to be candidates for nonsense-mediated decay (NMD). [provided by RefSeq, Oct 2013]

GCOM1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17359078).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYZAP	NM_001018100.5 linkuse as main transcript	c.1033G>T	p.Ala345Ser	missense_variant	10/13	ENST00000267853.10
GCOM1	NR_104367.2 linkuse as main transcript	n.1164G>T		non_coding_transcript_exon_variant	10/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYZAP	ENST00000267853.10 linkuse as main transcript	c.1033G>T	p.Ala345Ser	missense_variant	10/13	1	NM_001018100.5	P1	P0CAP1-1
MYZAP	ENST00000380565.8 linkuse as main transcript	c.1033G>T	p.Ala345Ser	missense_variant	10/12	1			P0CAP1-4
GCOM1	ENST00000649429.1 linkuse as main transcript	c.1033G>T	p.Ala345Ser	missense_variant	10/11
MYZAP	ENST00000461709.1 linkuse as main transcript	c.178G>T	p.Ala60Ser	missense_variant	3/5	3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152156

Hom.:

Cov.:

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461718

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727138

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:

0.0000126

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74326

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:

0.0000294

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 10, 2023

The c.1033G>T (p.A345S) alteration is located in exon 10 (coding exon 10) of the GCOM1 gene. This alteration results from a G to T substitution at nucleotide position 1033, causing the alanine (A) at amino acid position 345 to be replaced by a serine (S). 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

0.11

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

0.026

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.80

T;T;.;T;T;D;T

M_CAP

Benign

0.0061

MetaRNN

Benign

0.17

T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

0.52

D;D;D;D;D;D;D;D;D

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.30

N;.;.;N;N;N;N

REVEL

Benign

0.11

Sift

Benign

0.14

T;.;.;T;T;T;T

Sift4G

Benign

0.33

T;T;.;T;T;T;T

Polyphen

0.063, 0.20

.;.;.;.;B;B;.

Vest4

0.40

MutPred

0.096

Gain of phosphorylation at A345 (P = 0.0153);Gain of phosphorylation at A345 (P = 0.0153);Gain of phosphorylation at A345 (P = 0.0153);Gain of phosphorylation at A345 (P = 0.0153);Gain of phosphorylation at A345 (P = 0.0153);Gain of phosphorylation at A345 (P = 0.0153);.;

MVP

0.41

MPC

0.044

ClinPred

0.87

GERP RS

4.7

Varity_R

0.095

gMVP

0.19

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