15-57625843-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001018100.5(MYZAP):c.476G>A(p.Arg159His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000148 in 1,614,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R159L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: MYZAP NM_001018100.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.30

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]

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061270297).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYZAP	NM_001018100.5	c.476G>A	p.Arg159His	missense_variant	5/13	ENST00000267853.10
GCOM1	NR_104367.2	n.607G>A		non_coding_transcript_exon_variant	5/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYZAP	ENST00000267853.10	c.476G>A	p.Arg159His	missense_variant	5/13	1	NM_001018100.5	P1
MYZAP	ENST00000380565.8	c.476G>A	p.Arg159His	missense_variant	5/12	1
GCOM1	ENST00000649429.1	c.476G>A	p.Arg159His	missense_variant	5/11
MYZAP	ENST00000569089.1			downstream_gene_variant		4

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000155 AC: 39 AN: 251292 Hom.: 0 AF XY: 0.000162 AC XY: 22 AN XY: 135806

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000131 AC: 192 AN: 1461878 Hom.: 0 Cov.: 30 AF XY: 0.000136 AC XY: 99 AN XY: 727244

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000130

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74442

Gnomad4 AFR AF: 0.000891

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000105 Hom.: 0

Bravo AF: 0.000370

ESP6500AA AF: 0.000456 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000189 AC: 23

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 27, 2022

The c.476G>A (p.R159H) alteration is located in exon 5 (coding exon 5) of the GCOM1 gene. This alteration results from a G to A substitution at nucleotide position 476, causing the arginine (R) at amino acid position 159 to be replaced by a histidine (H). 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	0.061
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	20
Dann	Uncertain	0.98
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.12	T;T;.;T;T;T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.061	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;N;N;N;N;N;N;N;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.35	N;.;.;N;N;N
REVEL	Benign	0.091
Sift	Uncertain	0.017	D;.;.;D;D;D
Sift4G	Uncertain	0.019	D;D;.;D;D;D
Polyphen		0.63, 0.75	.;.;.;.;P;P
Vest4		0.11
MVP		0.17
MPC		0.078
ClinPred		0.017	T
GERP RS		3.9
Varity_R		0.029
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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

Other links and lift over

dbSNP: rs144926370; hg19: chr15-57918041;