rs143030509

Variant names:

• chr18-3134828-A-C
• rs143030509
• NM_003803.4:c.2210-4T>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003803.4(MYOM1):​c.2210-4T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,613,960 control chromosomes in the GnomAD database, including 138 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 0.0099 (10 hom., cov: 32)
  • Exomes 𝑓: 0.012 (128 hom.)
• Consequence: MYOM1 NM_003803.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002427
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.311
• 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 18-3134828-A-C is Benign according to our data. Variant chr18-3134828-A-C is described in ClinVar as Benign. ClinVar VariationId is 226811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 1504 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOM1	NM_003803.4	MANE Select	c.2210-4T>G		splice_region intron	N/A	NP_003794.3
	MYOM1	NM_019856.2		c.2210-4T>G		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.2210-4T>G		splice_region intron	N/A	ENSP00000348821.4	P52179-1
	MYOM1	ENST00000261606.11	TSL:1	c.2210-4T>G		splice_region intron	N/A	ENSP00000261606.7	P52179-2
	MYOM1	ENST00000941943.1		c.2210-4T>G		splice_region intron	N/A	ENSP00000612002.1

Frequencies

GnomAD3 genomes AF: 0.00988 AC: 1504 AN: 152190 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00635

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0272

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0146

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.0102 AC: 2534 AN: 249200 AF XY: 0.0101

Gnomad AFR exome AF: 0.00174

Gnomad AMR exome AF: 0.00319

Gnomad ASJ exome AF: 0.00726

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0287

Gnomad NFE exome AF: 0.0140

Gnomad OTH exome AF: 0.0121

GnomAD4 exome AF: 0.0116 AC: 17005 AN: 1461652 Hom.: 128 Cov.: 31 AF XY: 0.0114 AC XY: 8260 AN XY: 727118

African (AFR) AF: 0.00149 AC: 50 AN: 33480

American (AMR) AF: 0.00358 AC: 160 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00815 AC: 213 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00159 AC: 137 AN: 86256

European-Finnish (FIN) AF: 0.0268 AC: 1429 AN: 53402

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5768

European-Non Finnish (NFE) AF: 0.0130 AC: 14436 AN: 1111818

Other (OTH) AF: 0.00928 AC: 560 AN: 60368

GnomAD4 genome AF: 0.00987 AC: 1504 AN: 152308 Hom.: 10 Cov.: 32 AF XY: 0.0106 AC XY: 791 AN XY: 74482

African (AFR) AF: 0.00190 AC: 79 AN: 41550

American (AMR) AF: 0.00634 AC: 97 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00806 AC: 28 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4828

European-Finnish (FIN) AF: 0.0272 AC: 289 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0146 AC: 990 AN: 68032

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.0132 Hom.: 23

Bravo AF: 0.00763

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0106

EpiControl AF: 0.0117

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	MYOM1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.9
DANN	Benign	0.36
PhyloP100		-0.31
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000024
dbscSNV1_RF	Benign	0.0020
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: rs143030509; hg19: chr18-3134826;