18-3086067-C-T

Variant names:

• chr18-3086067-C-T
• rs3765623
• NM_003803.4:c.4222G>A

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.4222G>A​(p.Asp1408Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0769 in 1,607,392 control chromosomes in the GnomAD database, including 5,199 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1408Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.056 (308 hom., cov: 31)
  • Exomes 𝑓: 0.079 (4891 hom.)
• Consequence: MYOM1 NM_003803.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 7.88
• Publications: 20 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=0.0024063885).
• BP6: Variant 18-3086067-C-T is Benign according to our data. Variant chr18-3086067-C-T is described in ClinVar as Benign. ClinVar VariationId is 226822.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0772 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.4222G>A	p.Asp1408Asn	missense	Exon 30 of 38	NP_003794.3
	MYOM1	NM_019856.2		c.3934G>A	p.Asp1312Asn	missense	Exon 29 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.4222G>A	p.Asp1408Asn	missense	Exon 30 of 38	ENSP00000348821.4	P52179-1
	MYOM1	ENST00000261606.11	TSL:1	c.3934G>A	p.Asp1312Asn	missense	Exon 29 of 37	ENSP00000261606.7	P52179-2
	MYOM1	ENST00000941943.1		c.4186G>A	p.Asp1396Asn	missense	Exon 30 of 38	ENSP00000612002.1

Frequencies

GnomAD3 genomes AF: 0.0557 AC: 8472 AN: 152144 Hom.: 308 Cov.: 31

Gnomad AFR AF: 0.0132

Gnomad AMI AF: 0.0516

Gnomad AMR AF: 0.0617

Gnomad ASJ AF: 0.0257

Gnomad EAS AF: 0.0569

Gnomad SAS AF: 0.0829

Gnomad FIN AF: 0.0631

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0789

Gnomad OTH AF: 0.0474

GnomAD2 exomes AF: 0.0710 AC: 17568 AN: 247318 AF XY: 0.0725

Gnomad AFR exome AF: 0.0123

Gnomad AMR exome AF: 0.0772

Gnomad ASJ exome AF: 0.0235

Gnomad EAS exome AF: 0.0464

Gnomad FIN exome AF: 0.0701

Gnomad NFE exome AF: 0.0793

Gnomad OTH exome AF: 0.0667

GnomAD4 exome AF: 0.0791 AC: 115160 AN: 1455130 Hom.: 4891 Cov.: 29 AF XY: 0.0797 AC XY: 57693 AN XY: 724084

African (AFR) AF: 0.0113 AC: 378 AN: 33436

American (AMR) AF: 0.0778 AC: 3468 AN: 44588

Ashkenazi Jewish (ASJ) AF: 0.0241 AC: 629 AN: 26070

East Asian (EAS) AF: 0.0710 AC: 2809 AN: 39554

South Asian (SAS) AF: 0.0933 AC: 8008 AN: 85814

European-Finnish (FIN) AF: 0.0724 AC: 3741 AN: 51650

Middle Eastern (MID) AF: 0.0379 AC: 218 AN: 5758

European-Non Finnish (NFE) AF: 0.0829 AC: 91832 AN: 1108068

Other (OTH) AF: 0.0677 AC: 4077 AN: 60192

GnomAD4 genome AF: 0.0556 AC: 8471 AN: 152262 Hom.: 308 Cov.: 31 AF XY: 0.0549 AC XY: 4087 AN XY: 74456

African (AFR) AF: 0.0131 AC: 545 AN: 41550

American (AMR) AF: 0.0618 AC: 946 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0257 AC: 89 AN: 3466

East Asian (EAS) AF: 0.0573 AC: 297 AN: 5186

South Asian (SAS) AF: 0.0824 AC: 398 AN: 4832

European-Finnish (FIN) AF: 0.0631 AC: 669 AN: 10604

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0789 AC: 5369 AN: 68010

Other (OTH) AF: 0.0464 AC: 98 AN: 2110

Alfa AF: 0.0708 Hom.: 1915

Bravo AF: 0.0531

TwinsUK AF: 0.0860 AC: 319

ALSPAC AF: 0.0944 AC: 364

ESP6500AA AF: 0.0163 AC: 61

ESP6500EA AF: 0.0716 AC: 588

ExAC AF: 0.0727 AC: 8780

Asia WGS AF: 0.0620 AC: 219 AN: 3478

EpiCase AF: 0.0722

EpiControl AF: 0.0719

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.40
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.046	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.7	L
PhyloP100		7.9
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.21
Sift	Benign	0.076	T
Sift4G	Benign	0.13	T
Polyphen		0.79	P
Vest4		0.35
MPC		0.50
ClinPred		0.020	T
GERP RS		5.6
Varity_R		0.41
gMVP		0.77
Mutation Taster		=84/16	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs3765623; hg19: chr18-3086065; COSMIC: COSV55301857;