chr18-3100431-G-A

Variant names:

• chr18-3100431-G-A
• rs7232329
• NM_003803.4:c.3576-5C>T

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.3576-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.43 in 1,606,494 control chromosomes in the GnomAD database, including 152,167 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (11665 hom., cov: 31)
  • Exomes 𝑓: 0.44 (140502 hom.)
• Consequence: MYOM1 NM_003803.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001161
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0800
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 18-3100431-G-A is Benign according to our data. Variant chr18-3100431-G-A is described in ClinVar as Benign. ClinVar VariationId is 226819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.503 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOM1	NM_003803.4	MANE Select	c.3576-5C>T		splice_region intron	N/A	NP_003794.3
	MYOM1	NM_019856.2		c.3288-5C>T		splice_region intron	N/A	NP_062830.1	P52179-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOM1	ENST00000356443.9	TSL:1 MANE Select	c.3576-5C>T		splice_region intron	N/A	ENSP00000348821.4	P52179-1
	MYOM1	ENST00000261606.11	TSL:1	c.3288-5C>T		splice_region intron	N/A	ENSP00000261606.7	P52179-2
	MYOM1	ENST00000941943.1		c.3540-5C>T		splice_region intron	N/A	ENSP00000612002.1

Frequencies

GnomAD3 genomes AF: 0.373 AC: 56617 AN: 151778 Hom.: 11659 Cov.: 31

Gnomad AFR AF: 0.193

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.512

Gnomad ASJ AF: 0.456

Gnomad EAS AF: 0.354

Gnomad SAS AF: 0.359

Gnomad FIN AF: 0.355

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.449

Gnomad OTH AF: 0.445

GnomAD2 exomes AF: 0.427 AC: 104347 AN: 244570 AF XY: 0.426

Gnomad AFR exome AF: 0.188

Gnomad AMR exome AF: 0.578

Gnomad ASJ exome AF: 0.463

Gnomad EAS exome AF: 0.360

Gnomad FIN exome AF: 0.355

Gnomad NFE exome AF: 0.446

Gnomad OTH exome AF: 0.454

GnomAD4 exome AF: 0.436 AC: 633726 AN: 1454598 Hom.: 140502 Cov.: 31 AF XY: 0.435 AC XY: 314661 AN XY: 723666

African (AFR) AF: 0.183 AC: 6100 AN: 33284

American (AMR) AF: 0.570 AC: 25268 AN: 44334

Ashkenazi Jewish (ASJ) AF: 0.454 AC: 11802 AN: 26020

East Asian (EAS) AF: 0.345 AC: 13656 AN: 39602

South Asian (SAS) AF: 0.377 AC: 32288 AN: 85720

European-Finnish (FIN) AF: 0.357 AC: 19023 AN: 53220

Middle Eastern (MID) AF: 0.482 AC: 2776 AN: 5754

European-Non Finnish (NFE) AF: 0.449 AC: 497033 AN: 1106518

Other (OTH) AF: 0.429 AC: 25780 AN: 60146

GnomAD4 genome AF: 0.373 AC: 56644 AN: 151896 Hom.: 11665 Cov.: 31 AF XY: 0.370 AC XY: 27477 AN XY: 74204

African (AFR) AF: 0.193 AC: 7994 AN: 41436

American (AMR) AF: 0.512 AC: 7821 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.456 AC: 1582 AN: 3466

East Asian (EAS) AF: 0.355 AC: 1830 AN: 5154

South Asian (SAS) AF: 0.359 AC: 1727 AN: 4808

European-Finnish (FIN) AF: 0.355 AC: 3744 AN: 10532

Middle Eastern (MID) AF: 0.455 AC: 133 AN: 292

European-Non Finnish (NFE) AF: 0.449 AC: 30486 AN: 67924

Other (OTH) AF: 0.442 AC: 932 AN: 2108

Alfa AF: 0.422 Hom.: 10603

Bravo AF: 0.379

Asia WGS AF: 0.356 AC: 1240 AN: 3478

ClinVar

ClinVar submissions

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	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.4
DANN	Benign	0.31
PhyloP100		-0.080
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.0
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: rs7232329; hg19: chr18-3100429;