rs149528866

Variant names:

• chr18-3135646-C-T
• rs149528866
• NM_003803.4:c.2110G>A

Your query was ambiguous. Multiple possible variants found:

• chr18-3135646-C-T
• chr18-3135646-C-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.2110G>A​(p.Glu704Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00602 in 1,613,888 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E704D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0064 (13 hom., cov: 31)
  • Exomes 𝑓: 0.0060 (58 hom.)
• Consequence: MYOM1 NM_003803.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 7.91
• Publications: 9 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 (MetaRNN=0.011583).
• BP6: Variant 18-3135646-C-T is Benign according to our data. Variant chr18-3135646-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 974 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.2110G>A	p.Glu704Lys	missense	Exon 15 of 38	NP_003794.3
	MYOM1	NM_019856.2		c.2110G>A	p.Glu704Lys	missense	Exon 15 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.2110G>A	p.Glu704Lys	missense	Exon 15 of 38	ENSP00000348821.4	P52179-1
	MYOM1	ENST00000261606.11	TSL:1	c.2110G>A	p.Glu704Lys	missense	Exon 15 of 37	ENSP00000261606.7	P52179-2
	MYOM1	ENST00000941943.1		c.2110G>A	p.Glu704Lys	missense	Exon 15 of 38	ENSP00000612002.1

Frequencies

GnomAD3 genomes AF: 0.00640 AC: 974 AN: 152094 Hom.: 13 Cov.: 31

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0353

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00644

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00638 AC: 1589 AN: 249158 AF XY: 0.00621

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.0166

Gnomad EAS exome AF: 0.00184

Gnomad FIN exome AF: 0.0329

Gnomad NFE exome AF: 0.00512

Gnomad OTH exome AF: 0.00678

GnomAD4 exome AF: 0.00598 AC: 8736 AN: 1461676 Hom.: 58 Cov.: 30 AF XY: 0.00586 AC XY: 4263 AN XY: 727122

African (AFR) AF: 0.000717 AC: 24 AN: 33480

American (AMR) AF: 0.00183 AC: 82 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 422 AN: 26136

East Asian (EAS) AF: 0.000680 AC: 27 AN: 39698

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86250

European-Finnish (FIN) AF: 0.0341 AC: 1822 AN: 53398

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00531 AC: 5899 AN: 1111850

Other (OTH) AF: 0.00729 AC: 440 AN: 60372

GnomAD4 genome AF: 0.00640 AC: 974 AN: 152212 Hom.: 13 Cov.: 31 AF XY: 0.00735 AC XY: 547 AN XY: 74420

African (AFR) AF: 0.000843 AC: 35 AN: 41526

American (AMR) AF: 0.00321 AC: 49 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0173 AC: 60 AN: 3464

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.0353 AC: 374 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00644 AC: 438 AN: 68018

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00526 Hom.: 11

Bravo AF: 0.00371

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000257 AC: 1

ESP6500EA AF: 0.00387 AC: 32

ExAC AF: 0.00576 AC: 696

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00540

EpiControl AF: 0.00362

ClinVar

ClinVar submissions

Significance: Benign/Likely 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	MYOM1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.065	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.84	L
PhyloP100		7.9
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.38
Sift	Benign	0.057	T
Sift4G	Benign	0.21	T
Polyphen		1.0	D
Vest4		0.89
MVP		0.89
MPC		0.66
ClinPred		0.055	T
GERP RS		6.0
Varity_R		0.38
gMVP		0.71
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs149528866; hg19: chr18-3135644; COSMIC: COSV106083478;