chr18-3099683-G-A

Variant names:

• chr18-3099683-G-A
• rs4798067
• NM_003803.4:c.3727+476C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003803.4(MYOM1):​c.3727+476C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.8 in 152,192 control chromosomes in the GnomAD database, including 48,842 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.80 (48842 hom., cov: 32)
• Consequence: MYOM1 NM_003803.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.01
• Publications: 2 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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.826 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYOM1	NM_003803.4	c.3727+476C>T		intron_variant	Intron 25 of 37	ENST00000356443.9	NP_003794.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYOM1	ENST00000356443.9	c.3727+476C>T		intron_variant	Intron 25 of 37	1	NM_003803.4	ENSP00000348821.4
MYOM1	ENST00000261606.11	c.3439+476C>T		intron_variant	Intron 24 of 36	1		ENSP00000261606.7

Frequencies

GnomAD3 genomes AF: 0.800 AC: 121659 AN: 152074 Hom.: 48824 Cov.: 32

Gnomad AFR AF: 0.718

Gnomad AMI AF: 0.811

Gnomad AMR AF: 0.820

Gnomad ASJ AF: 0.839

Gnomad EAS AF: 0.804

Gnomad SAS AF: 0.781

Gnomad FIN AF: 0.872

Gnomad MID AF: 0.823

Gnomad NFE AF: 0.832

Gnomad OTH AF: 0.825

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.800 AC: 121731 AN: 152192 Hom.: 48842 Cov.: 32 AF XY: 0.801 AC XY: 59611 AN XY: 74398

African (AFR) AF: 0.718 AC: 29806 AN: 41492

American (AMR) AF: 0.820 AC: 12547 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.839 AC: 2914 AN: 3472

East Asian (EAS) AF: 0.804 AC: 4165 AN: 5182

South Asian (SAS) AF: 0.781 AC: 3769 AN: 4828

European-Finnish (FIN) AF: 0.872 AC: 9238 AN: 10598

Middle Eastern (MID) AF: 0.816 AC: 240 AN: 294

European-Non Finnish (NFE) AF: 0.832 AC: 56571 AN: 68004

Other (OTH) AF: 0.823 AC: 1741 AN: 2116

Alfa AF: 0.824 Hom.: 66713

Bravo AF: 0.793

Asia WGS AF: 0.765 AC: 2657 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.71
DANN	Benign	0.42
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs4798067; hg19: chr18-3099681;