18-3112408-C-T

Variant names:

• chr18-3112408-C-T
• rs186972208
• NM_003803.4:c.3308G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_003803.4(MYOM1):​c.3308G>A​(p.Arg1103Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000513 in 1,596,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1103P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: MYOM1 NM_003803.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.506
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.054264903).
• BP6: Variant 18-3112408-C-T is Benign according to our data. Variant chr18-3112408-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 227700.
• BS2: High AC in GnomAdExome4 at 79 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOM1	NM_003803.4	MANE Select	c.3308G>A	p.Arg1103Gln	missense	Exon 22 of 38	NP_003794.3
	MYOM1	NM_019856.2		c.3020G>A	p.Arg1007Gln	missense	Exon 21 of 37	NP_062830.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOM1	ENST00000356443.9	TSL:1 MANE Select	c.3308G>A	p.Arg1103Gln	missense	Exon 22 of 38	ENSP00000348821.4
	MYOM1	ENST00000261606.11	TSL:1	c.3020G>A	p.Arg1007Gln	missense	Exon 21 of 37	ENSP00000261606.7
	MYOM1	ENST00000941943.1		c.3272G>A	p.Arg1091Gln	missense	Exon 22 of 38	ENSP00000612002.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152164 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000333 AC: 8 AN: 240370 AF XY: 0.0000230

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000548

Gnomad OTH exome AF: 0.000347

GnomAD4 exome AF: 0.0000547 AC: 79 AN: 1444646 Hom.: 0 Cov.: 30 AF XY: 0.0000530 AC XY: 38 AN XY: 717210

African (AFR) AF: 0.0000907 AC: 3 AN: 33094

American (AMR) AF: 0.00 AC: 0 AN: 43392

Ashkenazi Jewish (ASJ) AF: 0.0000394 AC: 1 AN: 25386

East Asian (EAS) AF: 0.00 AC: 0 AN: 39320

South Asian (SAS) AF: 0.00 AC: 0 AN: 84318

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53060

Middle Eastern (MID) AF: 0.00370 AC: 21 AN: 5672

European-Non Finnish (NFE) AF: 0.0000481 AC: 53 AN: 1100812

Other (OTH) AF: 0.0000168 AC: 1 AN: 59592

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152282 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74456

African (AFR) AF: 0.00 AC: 0 AN: 41554

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000837 Hom.: 0

Bravo AF: 0.0000718

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.0000331 AC: 4

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	15
DANN	Benign	0.92
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.17	N
PhyloP100		0.51
PrimateAI	Benign	0.19	T
PROVEAN	Benign	0.38	N
REVEL	Benign	0.048
Sift	Benign	0.76	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.15
MVP		0.57
MPC		0.16
ClinPred		0.040	T
GERP RS		1.1
Varity_R		0.030
gMVP		0.096
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs186972208; hg19: chr18-3112406; COSMIC: COSV55296309;