NM_003803.4:c.4776C>G

Variant names:

• chr18-3067544-G-C
• rs1143658
• NM_003803.4:c.4776C>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_003803.4(MYOM1):​c.4776C>G​(p.Leu1592Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 1,611,646 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (1 hom.)
• Consequence: MYOM1 NM_003803.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 18-3067544-G-C is Benign according to our data. Variant chr18-3067544-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.01 with no splicing effect.
• BS2: High AC in GnomAd4 at 211 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.4776C>G	p.Leu1592Leu	synonymous	Exon 38 of 38	NP_003794.3
	MYOM1	NM_019856.2		c.4488C>G	p.Leu1496Leu	synonymous	Exon 37 of 37	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.4776C>G	p.Leu1592Leu	synonymous	Exon 38 of 38	ENSP00000348821.4	P52179-1
	MYOM1	ENST00000261606.11	TSL:1	c.4488C>G	p.Leu1496Leu	synonymous	Exon 37 of 37	ENSP00000261606.7	P52179-2
	MYOM1	ENST00000941943.1		c.4740C>G	p.Leu1580Leu	synonymous	Exon 38 of 38	ENSP00000612002.1

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 211 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00254

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00142 AC: 354 AN: 248496 AF XY: 0.00129

Gnomad AFR exome AF: 0.000452

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.000797

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00223

Gnomad NFE exome AF: 0.00242

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00203 AC: 2963 AN: 1459312 Hom.: 1 Cov.: 33 AF XY: 0.00200 AC XY: 1448 AN XY: 725508

African (AFR) AF: 0.000329 AC: 11 AN: 33406

American (AMR) AF: 0.000313 AC: 14 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00123 AC: 32 AN: 26112

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39638

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.00238 AC: 127 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5612

European-Non Finnish (NFE) AF: 0.00243 AC: 2700 AN: 1110052

Other (OTH) AF: 0.00129 AC: 78 AN: 60252

GnomAD4 genome AF: 0.00139 AC: 211 AN: 152334 Hom.: 0 Cov.: 33 AF XY: 0.00110 AC XY: 82 AN XY: 74498

African (AFR) AF: 0.000241 AC: 10 AN: 41576

American (AMR) AF: 0.000131 AC: 2 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00188 AC: 20 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00254 AC: 173 AN: 68042

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00167 Hom.: 0

Bravo AF: 0.00126

EpiCase AF: 0.00174

EpiControl AF: 0.00190

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.8
DANN	Benign	0.58
PhyloP100		1.0
Mutation Taster		=100/0	polymorphism

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: rs1143658; hg19: chr18-3067542;