rs111567318

Variant summary

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

The NM_002472.3(MYH8):c.5513A>C(p.Glu1838Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00569 in 1,614,214 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0043 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0058 ( 41 hom. )

Consequence

MYH8
NM_002472.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 7.97

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 where missense usually causes diseases, MYH8

BP4

Computational evidence support a benign effect (MetaRNN=0.014253795).

BP6

Variant 17-10392597-T-G is Benign according to our data. Variant chr17-10392597-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 445512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10392597-T-G is described in Lovd as [Benign]. Variant chr17-10392597-T-G is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd at 660 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH8	NM_002472.3 linkuse as main transcript	c.5513A>C	p.Glu1838Ala	missense_variant	38/40	ENST00000403437.2
MYHAS	NR_125367.1 linkuse as main transcript	n.76+9390T>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.5513A>C	p.Glu1838Ala	missense_variant	38/40	5	NM_002472.3	P1
	ENST00000399342.6 linkuse as main transcript	n.76+9390T>G		intron_variant, non_coding_transcript_variant		3
	ENST00000581304.1 linkuse as main transcript	n.52+9390T>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00434

AC:

660

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00464

Gnomad ASJ

AF:

0.00518

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00245

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00703

Gnomad OTH

AF:

0.00575

GnomAD3 exomes

AF:

0.00476

AC:

1196

AN:

251482

Hom.:

AF XY:

0.00486

AC XY:

660

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.000984

Gnomad AMR exome

AF:

0.00330

Gnomad ASJ exome

AF:

0.00268

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00193

Gnomad FIN exome

AF:

0.00263

Gnomad NFE exome

AF:

0.00778

Gnomad OTH exome

AF:

0.00619

GnomAD4 exome

AF:

0.00583

AC:

8523

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00569

AC XY:

4141

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000717

Gnomad4 AMR exome

AF:

0.00331

Gnomad4 ASJ exome

AF:

0.00429

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00219

Gnomad4 FIN exome

AF:

0.00322

Gnomad4 NFE exome

AF:

0.00682

Gnomad4 OTH exome

AF:

0.00467

GnomAD4 genome

AF:

0.00433

AC:

660

AN:

152328

Hom.:

Cov.:

AF XY:

0.00380

AC XY:

283

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00106

Gnomad4 AMR

AF:

0.00464

Gnomad4 ASJ

AF:

0.00518

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.00245

Gnomad4 NFE

AF:

0.00703

Gnomad4 OTH

AF:

0.00569

Alfa

AF:

0.00641

Hom.:

Bravo

AF:

0.00429

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00756

AC:

ExAC

AF:

0.00521

AC:

632

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00627

EpiControl

AF:

0.00877

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	MYH8: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 29, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2021	See Variant Classification Assertion Criteria. -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

- -

MYH8-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 05, 2019

This variant is classified as likely 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

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.13

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.52

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.014

MetaSVM

Uncertain

0.39

MutationAssessor

Pathogenic

3.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0010

Sift4G

Benign

0.21

Polyphen

0.99

Vest4

0.48

MVP

0.90

MPC

0.45

ClinPred

0.0080

GERP RS

5.0

Varity_R

0.53

gMVP

0.49

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