17-10639154-T-G

Variant summary

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

The NM_002470.4(MYH3):c.3138A>C(p.Arg1046=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.675 in 1,613,870 control chromosomes in the GnomAD database, including 379,828 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R1046R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.57 ( 27831 hom., cov: 32)

Exomes 𝑓: 0.69 ( 351997 hom. )

Consequence

MYH3
NM_002470.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -6.14

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=-0.91).

BP6

Variant 17-10639154-T-G is Benign according to our data. Variant chr17-10639154-T-G is described in ClinVar as [Benign]. Clinvar id is 129656.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10639154-T-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-6.14 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.728 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MYH3	NM_002470.4 linkuse as main transcript	c.3138A>C	p.Arg1046=	synonymous_variant	25/41	ENST00000583535.6
MYH3	XM_011523870.4 linkuse as main transcript	c.3138A>C	p.Arg1046=	synonymous_variant	25/41
MYH3	XM_011523871.3 linkuse as main transcript	c.3138A>C	p.Arg1046=	synonymous_variant	25/41
MYH3	XM_047436127.1 linkuse as main transcript	c.3138A>C	p.Arg1046=	synonymous_variant	27/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH3	ENST00000583535.6 linkuse as main transcript	c.3138A>C	p.Arg1046=	synonymous_variant	25/41	5	NM_002470.4	P1

Frequencies

GnomAD3 genomes

AF:

0.573

AC:

87102

AN:

151978

Hom.:

27825

Cov.:

show subpopulations

Gnomad AFR

AF:

0.295

Gnomad AMI

AF:

0.743

Gnomad AMR

AF:

0.561

Gnomad ASJ

AF:

0.703

Gnomad EAS

AF:

0.371

Gnomad SAS

AF:

0.523

Gnomad FIN

AF:

0.707

Gnomad MID

AF:

0.547

Gnomad NFE

AF:

0.734

Gnomad OTH

AF:

0.591

GnomAD3 exomes

AF:

0.610

AC:

153443

AN:

251460

Hom.:

49779

AF XY:

0.622

AC XY:

84574

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.294

Gnomad AMR exome

AF:

0.467

Gnomad ASJ exome

AF:

0.708

Gnomad EAS exome

AF:

0.362

Gnomad SAS exome

AF:

0.538

Gnomad FIN exome

AF:

0.715

Gnomad NFE exome

AF:

0.728

Gnomad OTH exome

AF:

0.653

GnomAD4 exome

AF:

0.686

AC:

1002239

AN:

1461770

Hom.:

351997

Cov.:

AF XY:

0.684

AC XY:

497631

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.277

Gnomad4 AMR exome

AF:

0.480

Gnomad4 ASJ exome

AF:

0.705

Gnomad4 EAS exome

AF:

0.368

Gnomad4 SAS exome

AF:

0.539

Gnomad4 FIN exome

AF:

0.720

Gnomad4 NFE exome

AF:

0.729

Gnomad4 OTH exome

AF:

0.653

GnomAD4 genome

AF:

0.573

AC:

87135

AN:

152100

Hom.:

27831

Cov.:

AF XY:

0.568

AC XY:

42222

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.295

Gnomad4 AMR

AF:

0.561

Gnomad4 ASJ

AF:

0.703

Gnomad4 EAS

AF:

0.372

Gnomad4 SAS

AF:

0.522

Gnomad4 FIN

AF:

0.707

Gnomad4 NFE

AF:

0.734

Gnomad4 OTH

AF:

0.595

Alfa

AF:

0.687

Hom.:

51727

Bravo

AF:

0.547

Asia WGS

AF:

0.465

AC:

1621

AN:

3478

EpiCase

AF:

0.730

EpiControl

AF:

0.724

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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+	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Freeman-Sheldon syndrome

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Contractures, pterygia, and variable skeletal fusions syndrome 1B

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Arthrogryposis, distal, type 2B3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Freeman-Sheldon syndrome;C1867440:Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A;C5193098:Arthrogryposis, distal, type 2B3;C5193114:Contractures, pterygia, and variable skeletal fusions syndrome 1B

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 11, 2021

- -

Distal arthrogryposis type 2B1

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. -

Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

Cadd

Benign

0.20

Dann

Benign

0.61

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