18-3215160-C-G

Variant names:

• chr18-3215160-C-G
• rs1791085
• NM_003803.4:c.64G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003803.4(MYOM1):​c.64G>C​(p.Val22Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0968 in 1,613,376 control chromosomes in the GnomAD database, including 7,946 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V22G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.10 (847 hom., cov: 32)
  • Exomes 𝑓: 0.096 (7099 hom.)
• Consequence: MYOM1 NM_003803.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.12
• Publications: 13 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

ENSG00000265399 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012019873).
• BP6: Variant 18-3215160-C-G is Benign according to our data. Variant chr18-3215160-C-G is described in ClinVar as Benign. ClinVar VariationId is 226833.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.168 is higher than 0.05.

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.64G>C	p.Val22Leu	missense	Exon 2 of 38	NP_003794.3
	MYOM1	NM_019856.2		c.64G>C	p.Val22Leu	missense	Exon 2 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.64G>C	p.Val22Leu	missense	Exon 2 of 38	ENSP00000348821.4
	MYOM1	ENST00000261606.11	TSL:1	c.64G>C	p.Val22Leu	missense	Exon 2 of 37	ENSP00000261606.7
	ENSG00000265399	ENST00000580139.1	TSL:2	n.198-1832C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15707 AN: 152074 Hom.: 849 Cov.: 32

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.172

Gnomad AMR AF: 0.0928

Gnomad ASJ AF: 0.0816

Gnomad EAS AF: 0.177

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.0924

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0898

Gnomad OTH AF: 0.0846

GnomAD2 exomes AF: 0.0990 AC: 24499 AN: 247380 AF XY: 0.0989

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.0722

Gnomad ASJ exome AF: 0.0891

Gnomad EAS exome AF: 0.169

Gnomad FIN exome AF: 0.0974

Gnomad NFE exome AF: 0.0917

Gnomad OTH exome AF: 0.0967

GnomAD4 exome AF: 0.0961 AC: 140395 AN: 1461184 Hom.: 7099 Cov.: 33 AF XY: 0.0963 AC XY: 70015 AN XY: 726828

African (AFR) AF: 0.116 AC: 3891 AN: 33476

American (AMR) AF: 0.0726 AC: 3240 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.0932 AC: 2432 AN: 26108

East Asian (EAS) AF: 0.183 AC: 7242 AN: 39676

South Asian (SAS) AF: 0.111 AC: 9523 AN: 86134

European-Finnish (FIN) AF: 0.100 AC: 5348 AN: 53356

Middle Eastern (MID) AF: 0.0576 AC: 332 AN: 5766

European-Non Finnish (NFE) AF: 0.0920 AC: 102229 AN: 1111664

Other (OTH) AF: 0.102 AC: 6158 AN: 60354

GnomAD4 genome AF: 0.103 AC: 15710 AN: 152192 Hom.: 847 Cov.: 32 AF XY: 0.104 AC XY: 7714 AN XY: 74424

African (AFR) AF: 0.123 AC: 5093 AN: 41516

American (AMR) AF: 0.0928 AC: 1419 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0816 AC: 283 AN: 3470

East Asian (EAS) AF: 0.177 AC: 916 AN: 5164

South Asian (SAS) AF: 0.119 AC: 574 AN: 4828

European-Finnish (FIN) AF: 0.0924 AC: 980 AN: 10602

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0898 AC: 6104 AN: 68006

Other (OTH) AF: 0.0823 AC: 174 AN: 2114

Alfa AF: 0.0833 Hom.: 379

Bravo AF: 0.103

TwinsUK AF: 0.0868 AC: 322

ALSPAC AF: 0.0823 AC: 317

ESP6500AA AF: 0.119 AC: 501

ESP6500EA AF: 0.0859 AC: 729

ExAC AF: 0.102 AC: 12319

EpiCase AF: 0.0860

EpiControl AF: 0.0857

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	MYOM1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	18
DANN	Benign	0.64
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.7	N
PhyloP100		3.1
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.42	N
REVEL	Benign	0.086
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.054
MPC		0.14
ClinPred		0.0021	T
GERP RS		5.7
Varity_R		0.034
gMVP		0.35
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1791085; hg19: chr18-3215158; COSMIC: COSV55292864;