rs35962914

Positions:

chr17-10400439-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_002472.3(MYH8):c.3686T>C(p.Met1229Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.01 in 1,613,930 control chromosomes in the GnomAD database, including 109 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0072 ( 12 hom., cov: 32)

Exomes 𝑓: 0.010 ( 97 hom. )

Consequence

MYH8
NM_002472.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 9.06

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH8. . Gene score misZ 0.34953 (greater than the threshold 3.09). Trascript score misZ 3.2125 (greater than threshold 3.09). GenCC has associacion of gene with trismus-pseudocamptodactyly syndrome, Carney complex - trismus - pseudocamptodactyly syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.0093815625).

BP6

Variant 17-10400439-A-G is Benign according to our data. Variant chr17-10400439-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 129675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10400439-A-G is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 1093 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH8	NM_002472.3 linkuse as main transcript	c.3686T>C	p.Met1229Thr	missense_variant	27/40	ENST00000403437.2
MYHAS	NR_125367.1 linkuse as main transcript	n.77-5709A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
MYH8	ENST00000403437.2 linkuse as main transcript	c.3686T>C	p.Met1229Thr	missense_variant	27/40	5	NM_002472.3	P1
	ENST00000399342.6 linkuse as main transcript	n.77-5709A>G		intron_variant, non_coding_transcript_variant		3
	ENST00000581304.1 linkuse as main transcript	n.53-5709A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00718

AC:

1092

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00208

Gnomad AMI

AF:

0.0978

Gnomad AMR

AF:

0.00615

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00415

Gnomad FIN

AF:

0.00547

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0106

Gnomad OTH

AF:

0.00670

GnomAD3 exomes

AF:

0.00657

AC:

1652

AN:

251446

Hom.:

AF XY:

0.00685

AC XY:

931

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00172

Gnomad AMR exome

AF:

0.00332

Gnomad ASJ exome

AF:

0.00198

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00454

Gnomad FIN exome

AF:

0.00513

Gnomad NFE exome

AF:

0.0105

Gnomad OTH exome

AF:

0.00749

GnomAD4 exome

AF:

0.0103

AC:

15072

AN:

1461692

Hom.:

Cov.:

AF XY:

0.0101

AC XY:

7314

AN XY:

727156

show subpopulations

Gnomad4 AFR exome

AF:

0.00149

Gnomad4 AMR exome

AF:

0.00389

Gnomad4 ASJ exome

AF:

0.00172

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00496

Gnomad4 FIN exome

AF:

0.00532

Gnomad4 NFE exome

AF:

0.0121

Gnomad4 OTH exome

AF:

0.00954

GnomAD4 genome

AF:

0.00718

AC:

1093

AN:

152238

Hom.:

Cov.:

AF XY:

0.00647

AC XY:

482

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.00207

Gnomad4 AMR

AF:

0.00615

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00436

Gnomad4 FIN

AF:

0.00547

Gnomad4 NFE

AF:

0.0106

Gnomad4 OTH

AF:

0.00663

Alfa

AF:

0.00977

Hom.:

Bravo

AF:

0.00716

TwinsUK

AF:

0.0129

AC:

ALSPAC

AF:

0.0109

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.0120

AC:

103

ExAC

AF:

0.00666

AC:

808

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.0118

EpiControl

AF:

0.0109

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 21, 2022	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 22, 2016

- -

MYH8-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hecht syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hecht syndrome;C1837245:Carney complex - trismus - pseudocamptodactyly syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 16, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.50

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.69

MetaRNN

Benign

0.0094

MetaSVM

Benign

-0.43

MutationAssessor

Uncertain

2.6

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-3.5

REVEL

Uncertain

0.37

Sift

Pathogenic

0.0

Sift4G

Benign

0.59

Polyphen

0.044

Vest4

0.54

MVP

0.81

MPC

0.39

ClinPred

0.16

GERP RS

4.3

Varity_R

0.78

gMVP

0.57

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