chr15-57633641-T-C

Position:

chr15-57633641-T-C

Variant summary

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

The NM_001018100.5(MYZAP):c.833T>C(p.Ile278Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000112 in 1,613,276 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: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

MYZAP
NM_001018100.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.03

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=0.11626005).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYZAP	NM_001018100.5 linkuse as main transcript	c.833T>C	p.Ile278Thr	missense_variant	8/13	ENST00000267853.10
GCOM1	NR_104367.2 linkuse as main transcript	n.964T>C		non_coding_transcript_exon_variant	8/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYZAP	ENST00000267853.10 linkuse as main transcript	c.833T>C	p.Ile278Thr	missense_variant	8/13	1	NM_001018100.5	P1	P0CAP1-1
MYZAP	ENST00000380565.8 linkuse as main transcript	c.833T>C	p.Ile278Thr	missense_variant	8/12	1			P0CAP1-4
GCOM1	ENST00000649429.1 linkuse as main transcript	c.833T>C	p.Ile278Thr	missense_variant	8/11
MYZAP	ENST00000461709.1 linkuse as main transcript			upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000479

AC:

AN:

250550

Hom.:

AF XY:

0.0000443

AC XY:

AN XY:

135372

show subpopulations

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:

0.000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000116

AC:

169

AN:

1461044

Hom.:

Cov.:

AF XY:

0.000111

AC XY:

AN XY:

726750

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:

0.000148

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.0000482

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:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000180

Hom.:

Bravo

AF:

0.0000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

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

Sep 22, 2023

The c.833T>C (p.I278T) alteration is located in exon 8 (coding exon 8) of the GCOM1 gene. This alteration results from a T to C substitution at nucleotide position 833, causing the isoleucine (I) at amino acid position 278 to be replaced by a threonine (T). 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

0.20

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.021

.;.;.;.;T;.

Eigen

Benign

0.14

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.89

D;D;.;D;D;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.12

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

.;.;.;.;M;M

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-1.8

N;.;.;N;N;N

REVEL

Benign

0.097

Sift

Uncertain

0.0080

D;.;.;D;D;D

Sift4G

Benign

0.29

T;T;.;T;T;T

Polyphen

0.73, 0.91

.;.;.;.;P;P

Vest4

0.81

MVP

0.60

MPC

0.17

ClinPred

0.28

GERP RS

5.7

Varity_R

0.11

gMVP

0.45

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