rs557671408

Variant names:

• chr18-3119949-G-A
• rs557671408
• NM_003803.4:c.3038C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP3 BP4_Strong BP6 BS1 BS2

The NM_003803.4(MYOM1):​c.3038C>T​(p.Ala1013Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,610,118 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A1013A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00075 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (34 hom.)
• Consequence: MYOM1 NM_003803.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 9.77
• Publications: 1 publications found

Genes affected

MYOM1 (HGNC:7613): (myomesin 1) The giant protein titin, together with its associated proteins, interconnects the major structure of sarcomeres, the M bands and Z discs. The C-terminal end of the titin string extends into the M line, where it binds tightly to M-band constituents of apparent molecular masses of 190 kD (myomesin 1) and 165 kD (myomesin 2). This protein, myomesin 1, like myomesin 2, titin, and other myofibrillar proteins contains structural modules with strong homology to either fibronectin type III (motif I) or immunoglobulin C2 (motif II) domains. Myomesin 1 and myomesin 2 each have a unique N-terminal region followed by 12 modules of motif I or motif II, in the arrangement II-II-I-I-I-I-I-II-II-II-II-II. The two proteins share 50% sequence identity in this repeat-containing region. The head structure formed by these 2 proteins on one end of the titin string extends into the center of the M band. The integrating structure of the sarcomere arises from muscle-specific members of the superfamily of immunoglobulin-like proteins. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

MYOM1 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.011919409).
• BP6: Variant 18-3119949-G-A is Benign according to our data. Variant chr18-3119949-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 416053.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000749 (114/152268) while in subpopulation SAS AF = 0.0228 (110/4824). AF 95% confidence interval is 0.0193. There are 4 homozygotes in GnomAd4. There are 86 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 114 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003803.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOM1	NM_003803.4	MANE Select	c.3038C>T	p.Ala1013Val	missense	Exon 20 of 38	NP_003794.3
	MYOM1	NM_019856.2		c.2750C>T	p.Ala917Val	missense	Exon 19 of 37	NP_062830.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOM1	ENST00000356443.9	TSL:1 MANE Select	c.3038C>T	p.Ala1013Val	missense	Exon 20 of 38	ENSP00000348821.4
	MYOM1	ENST00000261606.11	TSL:1	c.2750C>T	p.Ala917Val	missense	Exon 19 of 37	ENSP00000261606.7
	MYOM1	ENST00000582016.1	TSL:4	n.*23C>T		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.000756 AC: 115 AN: 152152 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0230

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.00268 AC: 648 AN: 241620 AF XY: 0.00359

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000300

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000571

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00119

GnomAD4 exome AF: 0.00121 AC: 1768 AN: 1457850 Hom.: 34 Cov.: 30 AF XY: 0.00172 AC XY: 1250 AN XY: 724822

African (AFR) AF: 0.0000299 AC: 1 AN: 33436

American (AMR) AF: 0.0000227 AC: 1 AN: 44038

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26034

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39610

South Asian (SAS) AF: 0.0196 AC: 1681 AN: 85548

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53124

Middle Eastern (MID) AF: 0.00106 AC: 6 AN: 5666

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1110164

Other (OTH) AF: 0.00123 AC: 74 AN: 60230

GnomAD4 genome AF: 0.000749 AC: 114 AN: 152268 Hom.: 4 Cov.: 32 AF XY: 0.00116 AC XY: 86 AN XY: 74448

African (AFR) AF: 0.0000241 AC: 1 AN: 41560

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.0228 AC: 110 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.0000775 Hom.: 0

Bravo AF: 0.000117

ExAC AF: 0.00295 AC: 356

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.97	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		9.8
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.77		Gain of catalytic residue at A1013 (P = 0.1121)
MVP		0.94
MPC		0.62
ClinPred		0.22	T
GERP RS		5.3
Varity_R		0.96
gMVP		0.91
Mutation Taster		=75/25	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: rs557671408; hg19: chr18-3119947;