18-3176042-C-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BA1

The NM_003803.4(MYOM1):​c.1022G>C​(p.Gly341Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.726 in 1,549,978 control chromosomes in the GnomAD database, including 410,464 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/23 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 Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G341E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.75 (42873 hom., cov: 32)
  • Exomes 𝑓: 0.72 (367591 hom.)
• Consequence: MYOM1 NM_003803.4 missense, splice_region
• Scores: Splicing: ADA: 0.9992
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• 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: Benign. The variant received -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 18-3176042-C-G is Benign according to our data. Variant chr18-3176042-C-G is described in ClinVar as Benign. ClinVar VariationId is 226796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.795 is higher than 0.05.

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>C	p.Gly341Ala	missense splice_region	Exon 6 of 38	NP_003794.3
	MYOM1	NM_019856.2		c.1022G>C	p.Gly341Ala	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>C	p.Gly341Ala	missense splice_region	Exon 6 of 38	ENSP00000348821.4	P52179-1
	MYOM1	ENST00000261606.11	TSL:1	c.1022G>C	p.Gly341Ala	missense splice_region	Exon 6 of 37	ENSP00000261606.7	P52179-2
	MYOM1	ENST00000941943.1		c.1022G>C	p.Gly341Ala	missense splice_region	Exon 6 of 38	ENSP00000612002.1

Frequencies

GnomAD3 genomes AF: 0.749 AC: 113909 AN: 152052 Hom.: 42804 Cov.: 32

Gnomad AFR AF: 0.802

Gnomad AMI AF: 0.733

Gnomad AMR AF: 0.751

Gnomad ASJ AF: 0.695

Gnomad EAS AF: 0.762

Gnomad SAS AF: 0.784

Gnomad FIN AF: 0.765

Gnomad MID AF: 0.691

Gnomad NFE AF: 0.714

Gnomad OTH AF: 0.746

GnomAD2 exomes AF: 0.742 AC: 182610 AN: 245946 AF XY: 0.741

Gnomad AFR exome AF: 0.805

Gnomad AMR exome AF: 0.775

Gnomad ASJ exome AF: 0.695

Gnomad EAS exome AF: 0.751

Gnomad FIN exome AF: 0.771

Gnomad NFE exome AF: 0.708

Gnomad OTH exome AF: 0.727

GnomAD4 exome AF: 0.724 AC: 1011443 AN: 1397806 Hom.: 367591 Cov.: 25 AF XY: 0.725 AC XY: 506872 AN XY: 698758

African (AFR) AF: 0.803 AC: 25851 AN: 32194

American (AMR) AF: 0.771 AC: 34182 AN: 44316

Ashkenazi Jewish (ASJ) AF: 0.694 AC: 17781 AN: 25610

East Asian (EAS) AF: 0.786 AC: 30937 AN: 39340

South Asian (SAS) AF: 0.793 AC: 67019 AN: 84484

European-Finnish (FIN) AF: 0.770 AC: 40912 AN: 53116

Middle Eastern (MID) AF: 0.640 AC: 3614 AN: 5644

European-Non Finnish (NFE) AF: 0.710 AC: 749121 AN: 1054840

Other (OTH) AF: 0.721 AC: 42026 AN: 58262

GnomAD4 genome AF: 0.749 AC: 114035 AN: 152172 Hom.: 42873 Cov.: 32 AF XY: 0.750 AC XY: 55790 AN XY: 74380

African (AFR) AF: 0.802 AC: 33300 AN: 41512

American (AMR) AF: 0.751 AC: 11490 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.695 AC: 2413 AN: 3472

East Asian (EAS) AF: 0.762 AC: 3941 AN: 5172

South Asian (SAS) AF: 0.784 AC: 3783 AN: 4824

European-Finnish (FIN) AF: 0.765 AC: 8102 AN: 10586

Middle Eastern (MID) AF: 0.694 AC: 204 AN: 294

European-Non Finnish (NFE) AF: 0.714 AC: 48557 AN: 67998

Other (OTH) AF: 0.749 AC: 1578 AN: 2108

Alfa AF: 0.711 Hom.: 26400

Bravo AF: 0.749

TwinsUK AF: 0.717 AC: 2660

ALSPAC AF: 0.724 AC: 2790

ESP6500AA AF: 0.808 AC: 3239

ESP6500EA AF: 0.716 AC: 5968

ExAC AF: 0.738 AC: 89145

Asia WGS AF: 0.803 AC: 2790 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	15
DANN	Benign	0.22
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.055	T
MetaRNN	Benign	8.3e-7	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.62	N
PhyloP100		0.17
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.65	N
REVEL	Benign	0.16
Sift	Benign	0.80	T
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.051
MPC		0.15
ClinPred		0.0035	T
GERP RS		2.0
Varity_R		0.11
gMVP		0.26
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.75
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; COSMIC: COSV55285904;