18-3102510-T-C

Position:

• chr18-3102510-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_003803.4(MYOM1):​c.3539A>G​(p.Asp1180Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000284 in 1,613,292 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: MYOM1 NM_003803.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 5.16

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009597391).
• BP6: Variant 18-3102510-T-C is Benign according to our data. Variant chr18-3102510-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227701.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=1}. Variant chr18-3102510-T-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYOM1	NM_003803.4	c.3539A>G	p.Asp1180Gly	missense_variant	23/38	ENST00000356443.9	NP_003794.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYOM1	ENST00000356443.9	c.3539A>G	p.Asp1180Gly	missense_variant	23/38	1	NM_003803.4	ENSP00000348821.4
MYOM1	ENST00000261606.11	c.3251A>G	p.Asp1084Gly	missense_variant	22/37	1		ENSP00000261606.7

Frequencies

GnomAD3 genomes AF: 0.00155 AC: 236 AN: 151832 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00540

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000788

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000386 AC: 96 AN: 248984 Hom.: 0 AF XY: 0.000289 AC XY: 39 AN XY: 135086

Gnomad AFR exome AF: 0.00536

Gnomad AMR exome AF: 0.000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000151 AC: 221 AN: 1461342 Hom.: 1 Cov.: 30 AF XY: 0.000131 AC XY: 95 AN XY: 726974

Gnomad4 AFR exome AF: 0.00526

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.000365

GnomAD4 genome AF: 0.00156 AC: 237 AN: 151950 Hom.: 1 Cov.: 32 AF XY: 0.00155 AC XY: 115 AN XY: 74278

Gnomad4 AFR AF: 0.00541

Gnomad4 AMR AF: 0.000787

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000472 Hom.: 0

Bravo AF: 0.00176

ESP6500AA AF: 0.00476 AC: 18

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000455 AC: 55

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 23, 2022	The p.D1180G variant (also known as c.3539A>G), located in coding exon 22 of the MYOM1 gene, results from an A to G substitution at nucleotide position 3539. The aspartic acid at codon 1180 is replaced by glycine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 13, 2015	p.Asp1180Gly in exon 23 of MYOM1: This variant is not expected to have clinical significance because it has been identified in 0.5% (51/9800) of African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs188319622). -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	MYOM1 NM_003803.3 exon 23 p.Asp1180Gly (c.3539A>G): This variant has not been reported in the literature and is present in 0.5% (137/24170) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/18-3102508-T-C). This variant is present in ClinVar (Variation ID:227701). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hypertrophic cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0096	T;T;T
MetaSVM	Uncertain	-0.029	T
MutationAssessor	Uncertain	2.6	M;.;.
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-6.0	D;.;D
REVEL	Uncertain	0.30
Sift	Benign	0.051	T;.;T
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.99	D;.;D
Vest4		0.39
MVP		0.93
MPC		0.26
ClinPred		0.051	T
GERP RS		5.5
Varity_R		0.55
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs188319622; hg19: chr18-3102508;