15-57639459-G-T

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

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.58
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]
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]

Genome browser will be placed here

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
MYZAPNM_001018100.5 linkuse as main transcriptc.1033G>T p.Ala345Ser missense_variant 10/13 ENST00000267853.10
GCOM1NR_104367.2 linkuse as main transcriptn.1164G>T non_coding_transcript_exon_variant 10/16

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MYZAPENST00000267853.10 linkuse as main transcriptc.1033G>T p.Ala345Ser missense_variant 10/131 NM_001018100.5 P1P0CAP1-1
MYZAPENST00000380565.8 linkuse as main transcriptc.1033G>T p.Ala345Ser missense_variant 10/121 P0CAP1-4
GCOM1ENST00000649429.1 linkuse as main transcriptc.1033G>T p.Ala345Ser missense_variant 10/11
MYZAPENST00000461709.1 linkuse as main transcriptc.178G>T p.Ala60Ser missense_variant 3/53

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152156
Hom.:
0
Cov.:
32
show subpopulations
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
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:
0.0000126
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
show subpopulations
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
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 10, 2023The 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1415653671; hg19: chr15-57931657; API