15-57621678-G-A

Variant names:

• chr15-57621678-G-A
• rs369885749
• NM_001018100.5:c.389G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001018100.5(MYZAP):​c.389G>A​(p.Arg130Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R130P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: MYZAP NM_001018100.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.11
• Publications: 8 publications found

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]

GCOM1 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.028546125).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001018100.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYZAP	NM_001018100.5	MANE Select	c.389G>A	p.Arg130Gln	missense	Exon 4 of 13	NP_001018110.1	P0CAP1-1
	GCOM1	NM_001285900.3		c.389G>A	p.Arg130Gln	missense	Exon 4 of 15	NP_001272829.1	H8Y6P7
	GCOM1	NM_001018090.6		c.389G>A	p.Arg130Gln	missense	Exon 4 of 14	NP_001018100.1	P0CAP1-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYZAP	ENST00000267853.10	TSL:1 MANE Select	c.389G>A	p.Arg130Gln	missense	Exon 4 of 13	ENSP00000267853.5	P0CAP1-1
	GCOM1	ENST00000587652.5	TSL:2	c.389G>A	p.Arg130Gln	missense	Exon 4 of 15	ENSP00000465231.1	H8Y6P7
	MYZAP	ENST00000380565.8	TSL:1	c.389G>A	p.Arg130Gln	missense	Exon 4 of 12	ENSP00000369939.4	P0CAP1-4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251338 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461568 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727094

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111798

Other (OTH) AF: 0.0000166 AC: 1 AN: 60384

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	9.3
DANN	Benign	0.75
DEOGEN2	Benign	0.0021	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.34	N
PhyloP100		1.1
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.28	N
REVEL	Benign	0.023
Sift	Benign	0.59	T
Sift4G	Benign	0.69	T
Polyphen		0.013	B
Vest4		0.16
MutPred		0.44		Loss of MoRF binding (P = 0.0117)
MVP		0.11
MPC		0.040
ClinPred		0.016	T
GERP RS		-0.0031
Varity_R		0.030
gMVP		0.11
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs369885749; hg19: chr15-57913876; COSMIC: COSV51087839;