rs200480164

Variant names:

• chr18-3102477-T-C
• rs200480164
• NM_003803.4:c.3572A>G

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.3572A>G​(p.Asn1191Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000258 in 1,610,858 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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. N1191I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: MYOM1 NM_003803.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.20
• Publications: 0 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=0.009263873).
• BP6: Variant 18-3102477-T-C is Benign according to our data. Variant chr18-3102477-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 416039.
• BS2: High AC in GnomAd4 at 225 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.3572A>G	p.Asn1191Ser	missense	Exon 23 of 38	NP_003794.3
	MYOM1	NM_019856.2		c.3284A>G	p.Asn1095Ser	missense	Exon 22 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.3572A>G	p.Asn1191Ser	missense	Exon 23 of 38	ENSP00000348821.4
	MYOM1	ENST00000261606.11	TSL:1	c.3284A>G	p.Asn1095Ser	missense	Exon 22 of 37	ENSP00000261606.7
	MYOM1	ENST00000941943.1		c.3536A>G	p.Asn1179Ser	missense	Exon 23 of 38	ENSP00000612002.1

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 224 AN: 152210 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00516

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

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: 0.000478

GnomAD2 exomes AF: 0.000352 AC: 87 AN: 246950 AF XY: 0.000269

Gnomad AFR exome AF: 0.00519

Gnomad AMR exome AF: 0.000177

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000130 AC: 190 AN: 1458530 Hom.: 0 Cov.: 31 AF XY: 0.0000993 AC XY: 72 AN XY: 725310

African (AFR) AF: 0.00492 AC: 164 AN: 33348

American (AMR) AF: 0.000226 AC: 10 AN: 44334

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25988

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.00 AC: 0 AN: 85676

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53330

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5750

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110200

Other (OTH) AF: 0.000199 AC: 12 AN: 60250

GnomAD4 genome AF: 0.00148 AC: 225 AN: 152328 Hom.: 3 Cov.: 32 AF XY: 0.00146 AC XY: 109 AN XY: 74486

African (AFR) AF: 0.00517 AC: 215 AN: 41572

American (AMR) AF: 0.000588 AC: 9 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000701 Hom.: 0

Bravo AF: 0.00179

ESP6500AA AF: 0.00445 AC: 17

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000439 AC: 53

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not specified (2)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	MYOM1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.062	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.2
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.075
Sift	Benign	0.24	T
Sift4G	Benign	0.47	T
Polyphen		0.0	B
Vest4		0.14
MVP		0.78
MPC		0.11
ClinPred		0.0086	T
GERP RS		3.0
Varity_R		0.099
gMVP		0.41
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs200480164; hg19: chr18-3102475; COSMIC: COSV108747403;