chr18-3187595-G-A

Position:

• chr18-3187595-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003803.4(MYOM1):​c.814C>T​(p.His272Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYOM1 NM_003803.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 2.27

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27563578).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYOM1	NM_003803.4	c.814C>T	p.His272Tyr	missense_variant	5/38	ENST00000356443.9	NP_003794.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYOM1	ENST00000356443.9	c.814C>T	p.His272Tyr	missense_variant	5/38	1	NM_003803.4	ENSP00000348821.4
MYOM1	ENST00000261606.11	c.814C>T	p.His272Tyr	missense_variant	5/37	1		ENSP00000261606.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460672 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726652

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

provider interpretation

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Jan 21, 2018

Variant p.His272Tyr in MYOM1 c.814C>T in exon 5 of MYOM1 (NM_003803.3, hg19, chr18-3187593-G-A) SCICD classification Variant of uncertain significance We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The rationale for this assessment is: lack of data to associate MYOM1 with HCM, the lack of data on this particular variant and its co-occurrence with a pathogenic variant in the same patient. Gene-level evidence MYOM1: MYOM1 encodes myomesin, a protein located in the M band of sarcomeres and is expressed in several isoforms of striated muscle. Myomesin dimers cross-link myosin (in the N-terminal domain 1) and titin (domains 4-6). Siegert et al (2011) identified a missense variant in MYOM1 in a proband with HCM. It segregated with disease in two other relatives. Per the ExAC database, MYOM1 appears to be tolerant of both missense (z=-0.35) and loss of function (pLI=0.00) variation. Given the lack of data to support the role of MYOM1 in HCM, we consider it a gene of uncertain significance. Case data summary Not reported in the literature. Not listed in ClinVar. Predicted Consequence Per the test report, "This sequence change replaces histidine with tyrosine at codon 272 of the MYOM1 protein (p.His272Tyr)." Experimental Data None reported In silico data Per the test report, "Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain." Conservation Per the test report, "The histidine residue is weakly conserved and there is a moderate physicochemical difference between histidine and tyrosine." The histidine at codon 272 is conserved in 37 of 100 total aligned species in the UCSC genome browser. It is weakly conserved. Nearby pathogenic variation There is no pathogenic variation listed at this codon or nearby codons in ClinVar. Population Data There is no variation at this codon in gnomAD. Metrics indicate adequate coverage. Please see below for details. Population data for p.His272Tyr in MYOM1: There is no variation at codon 272 listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. As of January 21, 2018 the average coverage at that site in gnomAD for exomes is: Mean coverage 63.2x, Median coverage 66x, and 97.53% of samples over 20x coverage. -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 07, 2017

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MYOM1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with tyrosine at codon 272 of the MYOM1 protein (p.His272Tyr). The histidine residue is weakly conserved and there is a moderate physicochemical difference between histidine and tyrosine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.030	T;.;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L;.;L
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.1	N;.;N
REVEL	Benign	0.059
Sift	Benign	0.070	T;.;T
Sift4G	Benign	0.077	T;T;T
Polyphen		0.36	B;.;P
Vest4		0.25
MutPred		0.45		Gain of sheet (P = 0.0149);.;Gain of sheet (P = 0.0149);
MVP		0.75
MPC		0.24
ClinPred		0.38	T
GERP RS		-1.0
Varity_R		0.086
gMVP		0.33

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555628272; hg19: chr18-3187593;