rs34088014

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_002470.4(MYH3):c.3008C>T(p.Ala1003Val) variant causes a missense change. The variant allele was found at a frequency of 0.0204 in 1,614,002 control chromosomes in the GnomAD database, including 359 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1003A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.022 ( 34 hom., cov: 32)

Exomes 𝑓: 0.020 ( 325 hom. )

Consequence

MYH3
NM_002470.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.86

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 -19 ACMG points.

PP2

Missense variant where missense usually causes diseases, MYH3

BP4

Computational evidence support a benign effect (MetaRNN=0.007245183).

BP6

Variant 17-10639392-G-A is Benign according to our data. Variant chr17-10639392-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 129654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10639392-G-A is described in Lovd as [Benign]. Variant chr17-10639392-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0218 (3324/152216) while in subpopulation AFR AF= 0.0309 (1283/41534). AF 95% confidence interval is 0.0295. There are 34 homozygotes in gnomad4. There are 1590 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High AC in GnomAd at 3318 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MYH3	NM_002470.4 linkuse as main transcript	c.3008C>T	p.Ala1003Val	missense_variant	24/41	ENST00000583535.6
MYH3	XM_011523870.4 linkuse as main transcript	c.3008C>T	p.Ala1003Val	missense_variant	24/41
MYH3	XM_011523871.3 linkuse as main transcript	c.3008C>T	p.Ala1003Val	missense_variant	24/41
MYH3	XM_047436127.1 linkuse as main transcript	c.3008C>T	p.Ala1003Val	missense_variant	26/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH3	ENST00000583535.6 linkuse as main transcript	c.3008C>T	p.Ala1003Val	missense_variant	24/41	5	NM_002470.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0218

AC:

3318

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0309

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0130

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.00270

Gnomad SAS

AF:

0.0268

Gnomad FIN

AF:

0.0192

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0210

Gnomad OTH

AF:

0.0210

GnomAD3 exomes

AF:

0.0181

AC:

4540

AN:

251224

Hom.:

AF XY:

0.0187

AC XY:

2543

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.0300

Gnomad AMR exome

AF:

0.00781

Gnomad ASJ exome

AF:

0.00873

Gnomad EAS exome

AF:

0.000980

Gnomad SAS exome

AF:

0.0293

Gnomad FIN exome

AF:

0.0176

Gnomad NFE exome

AF:

0.0201

Gnomad OTH exome

AF:

0.0188

GnomAD4 exome

AF:

0.0202

AC:

29558

AN:

1461786

Hom.:

325

Cov.:

AF XY:

0.0205

AC XY:

14875

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.0284

Gnomad4 AMR exome

AF:

0.00798

Gnomad4 ASJ exome

AF:

0.00838

Gnomad4 EAS exome

AF:

0.00592

Gnomad4 SAS exome

AF:

0.0288

Gnomad4 FIN exome

AF:

0.0165

Gnomad4 NFE exome

AF:

0.0209

Gnomad4 OTH exome

AF:

0.0192

GnomAD4 genome

AF:

0.0218

AC:

3324

AN:

152216

Hom.:

Cov.:

AF XY:

0.0214

AC XY:

1590

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.0309

Gnomad4 AMR

AF:

0.0130

Gnomad4 ASJ

AF:

0.00634

Gnomad4 EAS

AF:

0.00270

Gnomad4 SAS

AF:

0.0270

Gnomad4 FIN

AF:

0.0192

Gnomad4 NFE

AF:

0.0210

Gnomad4 OTH

AF:

0.0222

Alfa

AF:

0.0194

Hom.:

Bravo

AF:

0.0209

ESP6500AA

AF:

0.0293

AC:

129

ESP6500EA

AF:

0.0206

AC:

177

ExAC

AF:

0.0193

AC:

2338

Asia WGS

AF:

0.0370

AC:

129

AN:

3478

EpiCase

AF:

0.0208

EpiControl

AF:

0.0181

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 09, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Freeman-Sheldon 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. -

Distal arthrogryposis type 2B1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.040

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.61

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.0072

MetaSVM

Benign

-0.43

MutationAssessor

Benign

1.6

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.68

Sift4G

Benign

0.26

Polyphen

0.015

Vest4

0.097

MPC

0.88

ClinPred

0.016

GERP RS

5.5

Varity_R

0.35

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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