rs948299

Variant names:

• chr18-3087945-C-T
• rs948299
• NM_003803.4:c.4137+1229G>A

Variant summary

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

The NM_003803.4(MYOM1):​c.4137+1229G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.908 in 152,250 control chromosomes in the GnomAD database, including 62,893 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 0.91 (62893 hom., cov: 33)
• Consequence: MYOM1 NM_003803.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.231
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.928 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYOM1	NM_003803.4	c.4137+1229G>A		intron_variant	Intron 29 of 37	ENST00000356443.9	NP_003794.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYOM1	ENST00000356443.9	c.4137+1229G>A		intron_variant	Intron 29 of 37	1	NM_003803.4	ENSP00000348821.4
MYOM1	ENST00000261606.11	c.3849+1229G>A		intron_variant	Intron 28 of 36	1		ENSP00000261606.7
MYOM1	ENST00000581075.1	n.237+1229G>A		intron_variant	Intron 3 of 7	5		ENSP00000462039.1

Frequencies

GnomAD3 genomes AF: 0.908 AC: 138118 AN: 152132 Hom.: 62834 Cov.: 33

Gnomad AFR AF: 0.877

Gnomad AMI AF: 0.989

Gnomad AMR AF: 0.941

Gnomad ASJ AF: 0.944

Gnomad EAS AF: 0.739

Gnomad SAS AF: 0.863

Gnomad FIN AF: 0.940

Gnomad MID AF: 0.955

Gnomad NFE AF: 0.927

Gnomad OTH AF: 0.909

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

GnomAD4 genome AF: 0.908 AC: 138237 AN: 152250 Hom.: 62893 Cov.: 33 AF XY: 0.908 AC XY: 67551 AN XY: 74432

African (AFR) AF: 0.877 AC: 36436 AN: 41524

American (AMR) AF: 0.941 AC: 14393 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.944 AC: 3278 AN: 3472

East Asian (EAS) AF: 0.739 AC: 3829 AN: 5178

South Asian (SAS) AF: 0.864 AC: 4164 AN: 4818

European-Finnish (FIN) AF: 0.940 AC: 9966 AN: 10606

Middle Eastern (MID) AF: 0.955 AC: 279 AN: 292

European-Non Finnish (NFE) AF: 0.927 AC: 63065 AN: 68036

Other (OTH) AF: 0.911 AC: 1925 AN: 2114

Alfa AF: 0.923 Hom.: 105834

Bravo AF: 0.906

Asia WGS AF: 0.823 AC: 2865 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	4.5
DANN	Benign	0.80
PhyloP100		-0.23
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: rs948299; hg19: chr18-3087943;