15-57639459-G-T
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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
NM_001018100.5 missense
Scores
3
16
Clinical Significance
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]
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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 | 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: 2AN: 152156Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461718Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8AN XY: 727138
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152156Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74326
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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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
.;.;.;.;T;.;.
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;.;T;T;D;T
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;.;.;.;L;L;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;.;.;N;N;N;N
REVEL
Benign
Sift
Benign
T;.;.;T;T;T;T
Sift4G
Benign
T;T;.;T;T;T;T
Polyphen
0.063, 0.20
.;.;.;.;B;B;.
Vest4
MutPred
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
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at