rs56259391

Positions:

chr17-10641144-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002470.4(MYH3):c.2106C>T(p.Gly702=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0415 in 1,613,832 control chromosomes in the GnomAD database, including 1,896 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.058 ( 402 hom., cov: 32)

Exomes 𝑓: 0.040 ( 1494 hom. )

Consequence

MYH3
NM_002470.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.879

Variant links:

Genes affected

MYH3 (HGNC:7573): (myosin heavy chain 3) Myosin is a major contractile protein which converts chemical energy into mechanical energy through the hydrolysis of ATP. Myosin is a hexameric protein composed of a pair of myosin heavy chains (MYH) and two pairs of nonidentical light chains. This gene is a member of the MYH family and encodes a protein with an IQ domain and a myosin head-like domain. Mutations in this gene have been associated with two congenital contracture (arthrogryposis) syndromes, Freeman-Sheldon syndrome and Sheldon-Hall syndrome. [provided by RefSeq, Jul 2008]

MYH3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55).

BP6

Variant 17-10641144-G-A is Benign according to our data. Variant chr17-10641144-G-A is described in ClinVar as [Benign]. Clinvar id is 129648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10641144-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.879 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MYH3	NM_002470.4 linkuse as main transcript	c.2106C>T	p.Gly702=	synonymous_variant	19/41	ENST00000583535.6	NP_002461.2
MYH3	XM_011523870.4 linkuse as main transcript	c.2106C>T	p.Gly702=	synonymous_variant	19/41		XP_011522172.1
MYH3	XM_011523871.3 linkuse as main transcript	c.2106C>T	p.Gly702=	synonymous_variant	19/41		XP_011522173.1
MYH3	XM_047436127.1 linkuse as main transcript	c.2106C>T	p.Gly702=	synonymous_variant	21/43		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH3	ENST00000583535.6 linkuse as main transcript	c.2106C>T	p.Gly702=	synonymous_variant	19/41	5	NM_002470.4	ENSP00000464317	P1

Frequencies

GnomAD3 genomes

AF:

0.0583

AC:

8873

AN:

152126

Hom.:

402

Cov.:

show subpopulations

Gnomad AFR

AF:

0.127

Gnomad AMI

AF:

0.0482

Gnomad AMR

AF:

0.0276

Gnomad ASJ

AF:

0.0291

Gnomad EAS

AF:

0.00885

Gnomad SAS

AF:

0.0700

Gnomad FIN

AF:

0.0137

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0354

Gnomad OTH

AF:

0.0430

GnomAD3 exomes

AF:

0.0388

AC:

9752

AN:

251444

Hom.:

327

AF XY:

0.0383

AC XY:

5207

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.129

Gnomad AMR exome

AF:

0.0180

Gnomad ASJ exome

AF:

0.0240

Gnomad EAS exome

AF:

0.0105

Gnomad SAS exome

AF:

0.0663

Gnomad FIN exome

AF:

0.0161

Gnomad NFE exome

AF:

0.0352

Gnomad OTH exome

AF:

0.0354

GnomAD4 exome

AF:

0.0398

AC:

58099

AN:

1461588

Hom.:

1494

Cov.:

AF XY:

0.0397

AC XY:

28851

AN XY:

727122

show subpopulations

Gnomad4 AFR exome

AF:

0.132

Gnomad4 AMR exome

AF:

0.0183

Gnomad4 ASJ exome

AF:

0.0246

Gnomad4 EAS exome

AF:

0.00952

Gnomad4 SAS exome

AF:

0.0650

Gnomad4 FIN exome

AF:

0.0171

Gnomad4 NFE exome

AF:

0.0382

Gnomad4 OTH exome

AF:

0.0429

GnomAD4 genome

AF:

0.0583

AC:

8876

AN:

152244

Hom.:

402

Cov.:

AF XY:

0.0563

AC XY:

4193

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.127

Gnomad4 AMR

AF:

0.0276

Gnomad4 ASJ

AF:

0.0291

Gnomad4 EAS

AF:

0.00887

Gnomad4 SAS

AF:

0.0702

Gnomad4 FIN

AF:

0.0137

Gnomad4 NFE

AF:

0.0354

Gnomad4 OTH

AF:

0.0430

Alfa

AF:

0.0468

Hom.:

133

Bravo

AF:

0.0602

Asia WGS

AF:

0.0390

AC:

134

AN:

3478

EpiCase

AF:

0.0317

EpiControl

AF:

0.0331

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 26, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Freeman-Sheldon syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Distal arthrogryposis type 2B1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

6.9

DANN

Benign

0.52

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