rs1071600

Variant names:

• chr18-3126813-A-G
• rs1071600
• NM_003803.4:c.2879T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003803.4(MYOM1):​c.2879T>C​(p.Ile960Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,612,564 control chromosomes in the GnomAD database, including 23,059 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3268 hom., cov: 30)
  • Exomes 𝑓: 0.15 (19791 hom.)
• Consequence: MYOM1 NM_003803.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.467
• Publications: 26 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035020113).
• BP6: Variant 18-3126813-A-G is Benign according to our data. Variant chr18-3126813-A-G is described in ClinVar as Benign. ClinVar VariationId is 226815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.315 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.2879T>C	p.Ile960Thr	missense	Exon 19 of 38	NP_003794.3
	MYOM1	NM_019856.2		c.2591T>C	p.Ile864Thr	missense	Exon 18 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.2879T>C	p.Ile960Thr	missense	Exon 19 of 38	ENSP00000348821.4	P52179-1
	MYOM1	ENST00000261606.11	TSL:1	c.2591T>C	p.Ile864Thr	missense	Exon 18 of 37	ENSP00000261606.7	P52179-2
	MYOM1	ENST00000941943.1		c.2843T>C	p.Ile948Thr	missense	Exon 19 of 38	ENSP00000612002.1

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29647 AN: 151878 Hom.: 3249 Cov.: 30

Gnomad AFR AF: 0.265

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.210

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.328

Gnomad SAS AF: 0.247

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.203

GnomAD2 exomes AF: 0.193 AC: 47845 AN: 247648 AF XY: 0.193

Gnomad AFR exome AF: 0.268

Gnomad AMR exome AF: 0.232

Gnomad ASJ exome AF: 0.156

Gnomad EAS exome AF: 0.320

Gnomad FIN exome AF: 0.184

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.184

GnomAD4 exome AF: 0.155 AC: 225949 AN: 1460568 Hom.: 19791 Cov.: 32 AF XY: 0.158 AC XY: 114469 AN XY: 726498

African (AFR) AF: 0.280 AC: 9352 AN: 33446

American (AMR) AF: 0.227 AC: 10112 AN: 44512

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 4118 AN: 26104

East Asian (EAS) AF: 0.322 AC: 12758 AN: 39644

South Asian (SAS) AF: 0.245 AC: 21083 AN: 86042

European-Finnish (FIN) AF: 0.174 AC: 9295 AN: 53364

Middle Eastern (MID) AF: 0.245 AC: 1410 AN: 5764

European-Non Finnish (NFE) AF: 0.133 AC: 147285 AN: 1111344

Other (OTH) AF: 0.175 AC: 10536 AN: 60348

GnomAD4 genome AF: 0.196 AC: 29716 AN: 151996 Hom.: 3268 Cov.: 30 AF XY: 0.200 AC XY: 14879 AN XY: 74290

African (AFR) AF: 0.265 AC: 11001 AN: 41436

American (AMR) AF: 0.211 AC: 3227 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 573 AN: 3468

East Asian (EAS) AF: 0.328 AC: 1689 AN: 5152

South Asian (SAS) AF: 0.246 AC: 1186 AN: 4816

European-Finnish (FIN) AF: 0.188 AC: 1994 AN: 10580

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.137 AC: 9313 AN: 67950

Other (OTH) AF: 0.211 AC: 445 AN: 2106

Alfa AF: 0.162 Hom.: 9046

Bravo AF: 0.200

TwinsUK AF: 0.135 AC: 502

ALSPAC AF: 0.129 AC: 498

ESP6500AA AF: 0.261 AC: 1017

ESP6500EA AF: 0.142 AC: 1175

ExAC AF: 0.193 AC: 23291

Asia WGS AF: 0.318 AC: 1105 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	0.16
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	5.6
DANN	Benign	0.60
DEOGEN2	Benign	0.023	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.47
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.052
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.034
MPC		0.18
ClinPred		0.00030	T
GERP RS		1.4
Varity_R		0.066
gMVP		0.43
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1071600; hg19: chr18-3126811; COSMIC: COSV55287620;