18-3176042-C-T

Variant names:

• chr18-3176042-C-T
• rs8099021
• NM_003803.4:c.1022G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003803.4(MYOM1):​c.1022G>A​(p.Gly341Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000284 in 1,408,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G341A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: MYOM1 NM_003803.4 missense, splice_region
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.168
• Publications: 28 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.1022G>A	p.Gly341Glu	missense splice_region	Exon 6 of 38	NP_003794.3
	MYOM1	NM_019856.2		c.1022G>A	p.Gly341Glu	missense splice_region	Exon 6 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.1022G>A	p.Gly341Glu	missense splice_region	Exon 6 of 38	ENSP00000348821.4	P52179-1
	MYOM1	ENST00000261606.11	TSL:1	c.1022G>A	p.Gly341Glu	missense splice_region	Exon 6 of 37	ENSP00000261606.7	P52179-2
	MYOM1	ENST00000941943.1		c.1022G>A	p.Gly341Glu	missense splice_region	Exon 6 of 38	ENSP00000612002.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000284 AC: 4 AN: 1408462 Hom.: 0 Cov.: 25 AF XY: 0.00000284 AC XY: 2 AN XY: 703850

African (AFR) AF: 0.00 AC: 0 AN: 32354

American (AMR) AF: 0.00 AC: 0 AN: 44526

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25784

East Asian (EAS) AF: 0.00 AC: 0 AN: 39428

South Asian (SAS) AF: 0.00 AC: 0 AN: 85048

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5676

European-Non Finnish (NFE) AF: 0.00000376 AC: 4 AN: 1063710

Other (OTH) AF: 0.00 AC: 0 AN: 58676

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 26400

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	17
DANN	Benign	0.35
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.19	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-0.12	N
PhyloP100		0.17
PrimateAI	Benign	0.25	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.17
Sift	Benign	0.60	T
Sift4G	Benign	0.10	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.68		Loss of sheet (P = 0.0817)
MVP		0.71
MPC		0.18
ClinPred		0.018	T
GERP RS		2.0
Varity_R		0.10
gMVP		0.30
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.030		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: rs8099021; hg19: chr18-3176040;