chr18-3089524-G-T

Position:

• chr18-3089524-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003803.4(MYOM1):​c.4069+13C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.802 in 1,595,004 control chromosomes in the GnomAD database, including 514,139 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (51010 hom., cov: 32)
  • Exomes 𝑓: 0.80 (463129 hom.)
• Consequence: MYOM1 NM_003803.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0790

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 18-3089524-G-T is Benign according to our data. Variant chr18-3089524-G-T is described in ClinVar as [Benign]. Clinvar id is 226821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.864 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOM1	NM_003803.4	c.4069+13C>A		intron_variant		ENST00000356443.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOM1	ENST00000356443.9	c.4069+13C>A		intron_variant		1	NM_003803.4	P2
MYOM1	ENST00000261606.11	c.3781+13C>A		intron_variant		1		A2
MYOM1	ENST00000581075.1	c.169+13C>A		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.819 AC: 124467 AN: 152058 Hom.: 50955 Cov.: 32

Gnomad AFR AF: 0.832

Gnomad AMI AF: 0.693

Gnomad AMR AF: 0.876

Gnomad ASJ AF: 0.840

Gnomad EAS AF: 0.742

Gnomad SAS AF: 0.755

Gnomad FIN AF: 0.840

Gnomad MID AF: 0.829

Gnomad NFE AF: 0.805

Gnomad OTH AF: 0.821

GnomAD3 exomes AF: 0.812 AC: 195058 AN: 240184 Hom.: 79531 AF XY: 0.807 AC XY: 105138 AN XY: 130346

Gnomad AFR exome AF: 0.835

Gnomad AMR exome AF: 0.908

Gnomad ASJ exome AF: 0.836

Gnomad EAS exome AF: 0.717

Gnomad SAS exome AF: 0.771

Gnomad FIN exome AF: 0.834

Gnomad NFE exome AF: 0.799

Gnomad OTH exome AF: 0.821

GnomAD4 exome AF: 0.800 AC: 1154821 AN: 1442828 Hom.: 463129 Cov.: 29 AF XY: 0.800 AC XY: 573775 AN XY: 717158

Gnomad4 AFR exome AF: 0.830

Gnomad4 AMR exome AF: 0.904

Gnomad4 ASJ exome AF: 0.836

Gnomad4 EAS exome AF: 0.752

Gnomad4 SAS exome AF: 0.775

Gnomad4 FIN exome AF: 0.834

Gnomad4 NFE exome AF: 0.796

Gnomad4 OTH exome AF: 0.805

GnomAD4 genome AF: 0.819 AC: 124584 AN: 152176 Hom.: 51010 Cov.: 32 AF XY: 0.821 AC XY: 61040 AN XY: 74386

Gnomad4 AFR AF: 0.832

Gnomad4 AMR AF: 0.876

Gnomad4 ASJ AF: 0.840

Gnomad4 EAS AF: 0.742

Gnomad4 SAS AF: 0.756

Gnomad4 FIN AF: 0.840

Gnomad4 NFE AF: 0.805

Gnomad4 OTH AF: 0.824

Alfa AF: 0.803 Hom.: 97379

Bravo AF: 0.820

Asia WGS AF: 0.770 AC: 2677 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

4069+13C>A in intron 28 of MYOM1: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus seq uence. It has been identified in 20.3% (1647/8114) of European American chromoso mes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs .washington.edu/EVS; dbSNP rs948298). -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Hypertrophic cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.5
DANN	Benign	0.24

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

Publications

LitVar

Other links and lift over

dbSNP: rs948298; hg19: chr18-3089522; COSMIC: COSV55292367; COSMIC: COSV55292367;