rs34693726

Positions:

chr17-10409155-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002472.3(MYH8):c.1907C>T(p.Ala636Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0576 in 1,613,654 control chromosomes in the GnomAD database, including 3,088 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.054 ( 248 hom., cov: 33)

Exomes 𝑓: 0.058 ( 2840 hom. )

Consequence

MYH8
NM_002472.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.49

Variant links:

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]

MYH8 links:

ENSG00000272736 (HGNC:):

ENSG00000272736 links:

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]

MYHAS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019810796).

BP6

Variant 17-10409155-G-A is Benign according to our data. Variant chr17-10409155-G-A is described in ClinVar as [Benign]. Clinvar id is 129671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10409155-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH8	NM_002472.3 link	c.1907C>T	p.Ala636Val	missense_variant	17/40	ENST00000403437.2	NP_002463.2	P13535
MYHAS	NR_125367.1 link	n.167+2917G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MYH8	ENST00000403437.2 link	c.1907C>T	p.Ala636Val	missense_variant	17/40	5	NM_002472.3	ENSP00000384330.2	P13535
ENSG00000272736	ENST00000399342.6 link	n.206+2878G>A		intron_variant		3
ENSG00000272736	ENST00000581304.1 link	n.143+2917G>A		intron_variant		3
MYHAS	ENST00000587182.2 link	n.155+2917G>A		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0535

AC:

8130

AN:

152048

Hom.:

245

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0418

Gnomad AMI

AF:

0.0581

Gnomad AMR

AF:

0.0475

Gnomad ASJ

AF:

0.0792

Gnomad EAS

AF:

0.0410

Gnomad SAS

AF:

0.120

Gnomad FIN

AF:

0.0529

Gnomad MID

AF:

0.0669

Gnomad NFE

AF:

0.0564

Gnomad OTH

AF:

0.0679

GnomAD3 exomes

AF:

0.0589

AC:

14805

AN:

251236

Hom.:

544

AF XY:

0.0624

AC XY:

8470

AN XY:

135834

show subpopulations

Gnomad AFR exome

AF:

0.0403

Gnomad AMR exome

AF:

0.0439

Gnomad ASJ exome

AF:

0.0800

Gnomad EAS exome

AF:

0.0357

Gnomad SAS exome

AF:

0.111

Gnomad FIN exome

AF:

0.0546

Gnomad NFE exome

AF:

0.0549

Gnomad OTH exome

AF:

0.0588

GnomAD4 exome

AF:

0.0581

AC:

84872

AN:

1461488

Hom.:

2840

Cov.:

AF XY:

0.0596

AC XY:

43357

AN XY:

727098

show subpopulations

Gnomad4 AFR exome

AF:

0.0432

Gnomad4 AMR exome

AF:

0.0443

Gnomad4 ASJ exome

AF:

0.0811

Gnomad4 EAS exome

AF:

0.0356

Gnomad4 SAS exome

AF:

0.109

Gnomad4 FIN exome

AF:

0.0538

Gnomad4 NFE exome

AF:

0.0554

Gnomad4 OTH exome

AF:

0.0610

GnomAD4 genome

AF:

0.0536

AC:

8152

AN:

152166

Hom.:

248

Cov.:

AF XY:

0.0549

AC XY:

4082

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.0421

Gnomad4 AMR

AF:

0.0475

Gnomad4 ASJ

AF:

0.0792

Gnomad4 EAS

AF:

0.0407

Gnomad4 SAS

AF:

0.121

Gnomad4 FIN

AF:

0.0529

Gnomad4 NFE

AF:

0.0564

Gnomad4 OTH

AF:

0.0682

Alfa

AF:

0.0550

Hom.:

388

Bravo

AF:

0.0508

TwinsUK

AF:

0.0520

AC:

193

ALSPAC

AF:

0.0522

AC:

201

ESP6500AA

AF:

0.0452

AC:

199

ESP6500EA

AF:

0.0610

AC:

525

ExAC

AF:

0.0591

AC:

7178

Asia WGS

AF:

0.0900

AC:

313

AN:

3478

EpiCase

AF:

0.0575

EpiControl

AF:

0.0577

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hecht syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.25

MetaRNN

Benign

0.0020

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.96

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.6

REVEL

Benign

0.17

Sift

Benign

0.048

Sift4G

Benign

0.44

Polyphen

0.0

Vest4

0.097

MPC

0.20

ClinPred

0.029

GERP RS

5.2

Varity_R

0.088

gMVP

0.15

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over