rs150008607

Variant names:

• chr17-10398875-G-A
• rs150008607
• NM_002472.3:c.3874C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_002472.3(MYH8):​c.3874C>T​(p.Arg1292*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000177 in 1,612,060 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: MYH8 NM_002472.3 stop_gained
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.611
• Publications: 4 publications found

Genes affected

MYH8 (HGNC:7578): (myosin heavy chain 8) Myosins are actin-based motor proteins that function in the generation of mechanical force in eukaryotic cells. Muscle myosins are heterohexamers composed of 2 myosin heavy chains and 2 pairs of nonidentical myosin light chains. This gene encodes a member of the class II or conventional myosin heavy chains, and functions in skeletal muscle contraction. This gene is predominantly expressed in fetal skeletal muscle. This gene is found in a cluster of myosin heavy chain genes on chromosome 17. A mutation in this gene results in trismus-pseudocamptodactyly syndrome. [provided by RefSeq, Sep 2009]

MYHAS (HGNC:50609): (myosin heavy chain gene cluster antisense RNA) Predicted to enable primary miRNA binding activity. Predicted to be involved in response to muscle activity and skeletal muscle fiber development. Predicted to act upstream of or within with a positive effect on gene expression. Predicted to be located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 46 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002472.3. 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
	MYH8	NM_002472.3	MANE Select	c.3874C>T	p.Arg1292*	stop_gained	Exon 29 of 40	NP_002463.2	P13535
	MYHAS	NR_125367.1		n.77-7273G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH8	ENST00000403437.2	TSL:5 MANE Select	c.3874C>T	p.Arg1292*	stop_gained	Exon 29 of 40	ENSP00000384330.2	P13535
	MYHAS	ENST00000399342.6	TSL:3	n.77-7273G>A		intron	N/A
	MYHAS	ENST00000581304.2	TSL:3	n.53-7273G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000303 AC: 46 AN: 151736 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000727

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00715

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000482

GnomAD2 exomes AF: 0.000707 AC: 177 AN: 250406 AF XY: 0.000598

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00892

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000164 AC: 239 AN: 1460210 Hom.: 1 Cov.: 32 AF XY: 0.000131 AC XY: 95 AN XY: 726534

African (AFR) AF: 0.0000299 AC: 1 AN: 33470

American (AMR) AF: 0.0000671 AC: 3 AN: 44722

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

East Asian (EAS) AF: 0.00471 AC: 187 AN: 39692

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86238

European-Finnish (FIN) AF: 0.0000192 AC: 1 AN: 52142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111710

Other (OTH) AF: 0.000513 AC: 31 AN: 60378

GnomAD4 genome AF: 0.000303 AC: 46 AN: 151850 Hom.: 0 Cov.: 32 AF XY: 0.000337 AC XY: 25 AN XY: 74206

African (AFR) AF: 0.0000725 AC: 3 AN: 41388

American (AMR) AF: 0.000131 AC: 2 AN: 15260

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

East Asian (EAS) AF: 0.00717 AC: 37 AN: 5160

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67980

Other (OTH) AF: 0.000477 AC: 1 AN: 2096

Alfa AF: 0.000269 Hom.: 1

Bravo AF: 0.000419

ExAC AF: 0.000593 AC: 72

Asia WGS AF: 0.00289 AC: 11 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Hecht syndrome;C1837245:Carney complex - trismus - pseudocamptodactyly syndrome (2)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.41
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.60	D
PhyloP100		0.61
Vest4		0.86
GERP RS		4.3
Mutation Taster		=82/118	disease causing (fs/PTC)

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: rs150008607; hg19: chr17-10302192; COSMIC: COSV67974521;