15-57639480-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001018100.5(MYZAP):c.1054C>T(p.Arg352Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,613,926 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000031 ( 1 hom. )
Consequence
MYZAP
NM_001018100.5 missense
NM_001018100.5 missense
Scores
5
8
4
Clinical Significance
Conservation
PhyloP100: 0.926
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 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYZAP | NM_001018100.5 | c.1054C>T | p.Arg352Trp | missense_variant | 10/13 | ENST00000267853.10 | |
GCOM1 | NR_104367.2 | n.1185C>T | non_coding_transcript_exon_variant | 10/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYZAP | ENST00000267853.10 | c.1054C>T | p.Arg352Trp | missense_variant | 10/13 | 1 | NM_001018100.5 | P1 | |
MYZAP | ENST00000380565.8 | c.1054C>T | p.Arg352Trp | missense_variant | 10/12 | 1 | |||
GCOM1 | ENST00000649429.1 | c.1054C>T | p.Arg352Trp | missense_variant | 10/11 | ||||
MYZAP | ENST00000461709.1 | c.199C>T | p.Arg67Trp | missense_variant | 3/5 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152144Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000319 AC: 8AN: 251068Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135674
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GnomAD4 exome AF: 0.0000315 AC: 46AN: 1461782Hom.: 1 Cov.: 30 AF XY: 0.0000261 AC XY: 19AN XY: 727196
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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 | Dec 09, 2023 | The c.1054C>T (p.R352W) alteration is located in exon 10 (coding exon 10) of the GCOM1 gene. This alteration results from a C to T substitution at nucleotide position 1054, causing the arginine (R) at amino acid position 352 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Pathogenic
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;.;D;D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.;.;D;D;D;D
REVEL
Uncertain
Sift
Pathogenic
D;.;.;D;D;D;D
Sift4G
Uncertain
D;D;.;D;D;D;D
Polyphen
1.0
.;.;.;.;D;D;.
Vest4
MutPred
Loss of disorder (P = 0.0756);Loss of disorder (P = 0.0756);Loss of disorder (P = 0.0756);Loss of disorder (P = 0.0756);Loss of disorder (P = 0.0756);Loss of disorder (P = 0.0756);.;
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