18-3141986-G-C

Variant names:

• chr18-3141986-G-C
• rs201104206
• NM_003803.4:c.1978C>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003803.4(MYOM1):​c.1978C>G​(p.Pro660Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000988 in 1,613,648 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P660S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00097 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00099 (1 hom.)
• Consequence: MYOM1 NM_003803.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2 B:5
• Conservation: PhyloP100: 10.0
• Publications: 6 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.050358325).
• BP6: Variant 18-3141986-G-C is Benign according to our data. Variant chr18-3141986-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 155822.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 147 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOM1	NM_003803.4	MANE Select	c.1978C>G	p.Pro660Ala	missense	Exon 14 of 38	NP_003794.3
	MYOM1	NM_019856.2		c.1978C>G	p.Pro660Ala	missense	Exon 14 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.1978C>G	p.Pro660Ala	missense	Exon 14 of 38	ENSP00000348821.4	P52179-1
	MYOM1	ENST00000261606.11	TSL:1	c.1978C>G	p.Pro660Ala	missense	Exon 14 of 37	ENSP00000261606.7	P52179-2
	MYOM1	ENST00000941943.1		c.1978C>G	p.Pro660Ala	missense	Exon 14 of 38	ENSP00000612002.1

Frequencies

GnomAD3 genomes AF: 0.000967 AC: 147 AN: 151944 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00265

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00140

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00105 AC: 262 AN: 249188 AF XY: 0.00106

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000753

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00330

Gnomad NFE exome AF: 0.00143

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000990 AC: 1447 AN: 1461586 Hom.: 1 Cov.: 30 AF XY: 0.00102 AC XY: 738 AN XY: 727086

African (AFR) AF: 0.000239 AC: 8 AN: 33476

American (AMR) AF: 0.000648 AC: 29 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00285 AC: 152 AN: 53388

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.00108 AC: 1203 AN: 1111796

Other (OTH) AF: 0.000895 AC: 54 AN: 60362

GnomAD4 genome AF: 0.000967 AC: 147 AN: 152062 Hom.: 0 Cov.: 31 AF XY: 0.000928 AC XY: 69 AN XY: 74324

African (AFR) AF: 0.000362 AC: 15 AN: 41452

American (AMR) AF: 0.000393 AC: 6 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00265 AC: 28 AN: 10586

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

European-Non Finnish (NFE) AF: 0.00140 AC: 95 AN: 67998

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000925 Hom.: 0

Bravo AF: 0.000778

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00157 AC: 13

ExAC AF: 0.00107 AC: 129

EpiCase AF: 0.00142

EpiControl AF: 0.00160

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	MYOM1-related disorder (1)
-	-	1	not specified (1)
-	1	-	Primary dilated cardiomyopathy (1)
-	1	-	Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.7	L
PhyloP100		10
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.42
Sift	Benign	0.046	D
Sift4G	Uncertain	0.046	D
Polyphen		1.0	D
Vest4		0.78
MVP		0.84
MPC		0.61
ClinPred		0.11	T
GERP RS		5.9
Varity_R		0.29
gMVP		0.51
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs201104206; hg19: chr18-3141984;