Variant 15-57621671-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001018100.5(MYZAP):c.382A>G(p.Lys128Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,676 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: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MYZAP
NM_001018100.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.82

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29378632).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYZAP	NM_001018100.5 linkuse as main transcript	c.382A>G	p.Lys128Glu	missense_variant	4/13	ENST00000267853.10
GCOM1	NR_104367.2 linkuse as main transcript	n.513A>G		non_coding_transcript_exon_variant	4/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYZAP	ENST00000267853.10 linkuse as main transcript	c.382A>G	p.Lys128Glu	missense_variant	4/13	1	NM_001018100.5	P1	P0CAP1-1
MYZAP	ENST00000380565.8 linkuse as main transcript	c.382A>G	p.Lys128Glu	missense_variant	4/12	1			P0CAP1-4
GCOM1	ENST00000649429.1 linkuse as main transcript	c.382A>G	p.Lys128Glu	missense_variant	4/11
MYZAP	ENST00000569089.1 linkuse as main transcript	c.337A>G	p.Lys113Glu	missense_variant	5/6	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461676

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727148

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Apr 13, 2022

The c.382A>G (p.K128E) alteration is located in exon 4 (coding exon 4) of the GCOM1 gene. This alteration results from a A to G substitution at nucleotide position 382, causing the lysine (K) at amino acid position 128 to be replaced by a glutamic acid (E). 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

0.25

BayesDel_addAF

Uncertain

0.017

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.011

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

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.91

D;D;.;D;D;D;D

M_CAP

Benign

0.066

MetaRNN

Benign

0.29

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

MetaSVM

Benign

-0.68

MutationAssessor

Benign

1.9

.;.;.;.;L;L;.

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.4

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

REVEL

Benign

0.074

Sift

Uncertain

0.0060

D;.;.;D;D;D;D

Sift4G

Benign

0.42

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

Polyphen

0.53, 1.0

.;.;.;.;P;D;.

Vest4

0.55

MutPred

0.46

Loss of MoRF binding (P = 0.0021);Loss of MoRF binding (P = 0.0021);Loss of MoRF binding (P = 0.0021);Loss of MoRF binding (P = 0.0021);Loss of MoRF binding (P = 0.0021);Loss of MoRF binding (P = 0.0021);.;

MVP

0.58

MPC

0.20

ClinPred

0.82

GERP RS

5.7

Varity_R

0.34

gMVP

0.49

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over