rs35230241

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_002470.4(MYH3):c.3938C>T(p.Thr1313Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00389 in 1,614,128 control chromosomes in the GnomAD database, including 175 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 96 hom., cov: 33)

Exomes 𝑓: 0.0022 ( 79 hom. )

Consequence

MYH3
NM_002470.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 2.19

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 in the MYH3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 36 curated pathogenic missense variants (we use a threshold of 10). The gene has 26 curated benign missense variants. Gene score misZ: 1.7445 (below the threshold of 3.09). Trascript score misZ: 4.649 (above the threshold of 3.09). GenCC associations: The gene is linked to spondylocarpotarsal synostosis syndrome, contractures, pterygia, and variable skeletal fusions syndrome 1B, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, digitotalar dysmorphism, autosomal recessive multiple pterygium syndrome, Freeman-Sheldon syndrome, distal arthrogryposis type 2B1, Sheldon-hall syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.0023226738).

BP6

Variant 17-10635772-G-A is Benign according to our data. Variant chr17-10635772-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 129660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10635772-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH3	NM_002470.4 link	c.3938C>T	p.Thr1313Ile	missense_variant	Exon 29 of 41	ENST00000583535.6	NP_002461.2	P11055Q5GJ67
MYH3	XM_011523870.4 link	c.3938C>T	p.Thr1313Ile	missense_variant	Exon 29 of 41		XP_011522172.1	P11055
MYH3	XM_011523871.3 link	c.3938C>T	p.Thr1313Ile	missense_variant	Exon 29 of 41		XP_011522173.1	P11055
MYH3	XM_047436127.1 link	c.3938C>T	p.Thr1313Ile	missense_variant	Exon 31 of 43		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH3	ENST00000583535.6 link	c.3938C>T	p.Thr1313Ile	missense_variant	Exon 29 of 41	5	NM_002470.4	ENSP00000464317.1		P11055

Frequencies

GnomAD3 genomes

AF:

0.0199

AC:

3025

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0681

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00851

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00289

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.00590

AC:

1485

AN:

251492

Hom.:

AF XY:

0.00420

AC XY:

571

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.0728

Gnomad AMR exome

AF:

0.00581

Gnomad ASJ exome

AF:

0.000694

Gnomad EAS exome

AF:

0.00109

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000334

Gnomad OTH exome

AF:

0.00423

GnomAD4 exome

AF:

0.00223

AC:

3255

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00191

AC XY:

1386

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0695

Gnomad4 AMR exome

AF:

0.00633

Gnomad4 ASJ exome

AF:

0.00119

Gnomad4 EAS exome

AF:

0.000730

Gnomad4 SAS exome

AF:

0.000556

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000178

Gnomad4 OTH exome

AF:

0.00517

GnomAD4 genome

AF:

0.0199

AC:

3032

AN:

152252

Hom.:

Cov.:

AF XY:

0.0186

AC XY:

1387

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.0679

Gnomad4 AMR

AF:

0.00850

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00289

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.0147

Alfa

AF:

0.00452

Hom.:

Bravo

AF:

0.0221

ESP6500AA

AF:

0.0744

AC:

328

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.00713

AC:

866

Asia WGS

AF:

0.0220

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 03, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 27, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Freeman-Sheldon syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.19

DEOGEN2

Benign

0.18

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.35

MetaRNN

Benign

0.0023

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.2

PrimateAI

Benign

0.44

Sift4G

Benign

0.38

Polyphen

0.0

Vest4

0.18

MVP

0.47

MPC

0.27

ClinPred

0.0067

GERP RS

2.9

Varity_R

0.036

gMVP

0.052

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