chr15-57639459-G-T

Position:

• chr15-57639459-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.58

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 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	c.1033G>T	p.Ala345Ser	missense_variant	10/13	ENST00000267853.10
GCOM1	NR_104367.2	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	c.1033G>T	p.Ala345Ser	missense_variant	10/13	1	NM_001018100.5	P1
MYZAP	ENST00000380565.8	c.1033G>T	p.Ala345Ser	missense_variant	10/12	1
GCOM1	ENST00000649429.1	c.1033G>T	p.Ala345Ser	missense_variant	10/11
MYZAP	ENST00000461709.1	c.178G>T	p.Ala60Ser	missense_variant	3/5	3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152156 Hom.: 0 Cov.: 32

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: 14 AN: 1461718 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 727138

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: 2 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74326

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

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	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0048	.;.;.;.;T;.;.
Eigen	Benign	0.026
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.80	T;T;.;T;T;D;T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.17	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	.;.;.;.;L;L;.
MutationTaster	Benign	0.52	D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.44	T
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	D
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

Other links and lift over

dbSNP: rs1415653671; hg19: chr15-57931657;