chr18-3215133-G-T

Variant names:

• chr18-3215133-G-T
• rs76382984
• NM_003803.4:c.91C>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003803.4(MYOM1):​c.91C>A​(p.Arg31Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 1,613,742 control chromosomes in the GnomAD database, including 265 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R31R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (25 hom., cov: 32)
  • Exomes 𝑓: 0.015 (240 hom.)
• Consequence: MYOM1 NM_003803.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.56
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 18-3215133-G-T is Benign according to our data. Variant chr18-3215133-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.56 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0126 (1912/152220) while in subpopulation EAS AF = 0.0416 (215/5166). AF 95% confidence interval is 0.0371. There are 25 homozygotes in GnomAd4. There are 990 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1912 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.91C>A	p.Arg31Arg	synonymous	Exon 2 of 38	NP_003794.3
	MYOM1	NM_019856.2		c.91C>A	p.Arg31Arg	synonymous	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.91C>A	p.Arg31Arg	synonymous	Exon 2 of 38	ENSP00000348821.4
	MYOM1	ENST00000261606.11	TSL:1	c.91C>A	p.Arg31Arg	synonymous	Exon 2 of 37	ENSP00000261606.7
	MYOM1	ENST00000941943.1		c.91C>A	p.Arg31Arg	synonymous	Exon 2 of 38	ENSP00000612002.1

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1911 AN: 152102 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.00205

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.00916

Gnomad ASJ AF: 0.0204

Gnomad EAS AF: 0.0413

Gnomad SAS AF: 0.00560

Gnomad FIN AF: 0.0333

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0143

Gnomad OTH AF: 0.0101

GnomAD2 exomes AF: 0.0172 AC: 4281 AN: 248290 AF XY: 0.0166

Gnomad AFR exome AF: 0.00202

Gnomad AMR exome AF: 0.0131

Gnomad ASJ exome AF: 0.0218

Gnomad EAS exome AF: 0.0409

Gnomad FIN exome AF: 0.0382

Gnomad NFE exome AF: 0.0154

Gnomad OTH exome AF: 0.0171

GnomAD4 exome AF: 0.0152 AC: 22255 AN: 1461522 Hom.: 240 Cov.: 33 AF XY: 0.0150 AC XY: 10894 AN XY: 727052

African (AFR) AF: 0.00170 AC: 57 AN: 33474

American (AMR) AF: 0.0132 AC: 591 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0219 AC: 573 AN: 26126

East Asian (EAS) AF: 0.0352 AC: 1397 AN: 39690

South Asian (SAS) AF: 0.00637 AC: 549 AN: 86228

European-Finnish (FIN) AF: 0.0398 AC: 2123 AN: 53348

Middle Eastern (MID) AF: 0.00486 AC: 28 AN: 5766

European-Non Finnish (NFE) AF: 0.0145 AC: 16077 AN: 1111826

Other (OTH) AF: 0.0142 AC: 860 AN: 60360

GnomAD4 genome AF: 0.0126 AC: 1912 AN: 152220 Hom.: 25 Cov.: 32 AF XY: 0.0133 AC XY: 990 AN XY: 74428

African (AFR) AF: 0.00205 AC: 85 AN: 41544

American (AMR) AF: 0.00915 AC: 140 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0204 AC: 71 AN: 3472

East Asian (EAS) AF: 0.0416 AC: 215 AN: 5166

South Asian (SAS) AF: 0.00581 AC: 28 AN: 4818

European-Finnish (FIN) AF: 0.0333 AC: 353 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0143 AC: 975 AN: 67990

Other (OTH) AF: 0.00950 AC: 20 AN: 2106

Alfa AF: 0.0147 Hom.: 28

Bravo AF: 0.0107

Asia WGS AF: 0.0210 AC: 72 AN: 3478

EpiCase AF: 0.0133

EpiControl AF: 0.0129

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	11
DANN	Benign	0.65
PhyloP100		3.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs76382984; hg19: chr18-3215131; COSMIC: COSV55303645;