17-10631643-C-T

Position:

chr17-10631643-C-T

Variant summary

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

The NM_002470.4(MYH3):c.5254G>A(p.Ala1752Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0203 in 1,614,110 control chromosomes in the GnomAD database, including 358 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 34 hom., cov: 32)

Exomes 𝑓: 0.020 ( 324 hom. )

Consequence

MYH3
NM_002470.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 4.88

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:

LOC124903927 (HGNC:):

LOC124903927 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 gene, where missense usually causes diseases (based on misZ statistic), MYH3. . Gene score misZ 1.7445 (greater than the threshold 3.09). Trascript score misZ 4.649 (greater than threshold 3.09). GenCC has associacion of gene with 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=0.0059009492).

BP6

Variant 17-10631643-C-T is Benign according to our data. Variant chr17-10631643-C-T is described in ClinVar as [Benign]. Clinvar id is 129664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10631643-C-T is described in Lovd as [Benign]. Variant chr17-10631643-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0218 (3323/152254) while in subpopulation AFR AF= 0.0309 (1284/41542). AF 95% confidence interval is 0.0295. There are 34 homozygotes in gnomad4. There are 1590 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 3323 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH3	NM_002470.4 linkuse as main transcript	c.5254G>A	p.Ala1752Thr	missense_variant	36/41	ENST00000583535.6	NP_002461.2	P11055Q5GJ67

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH3	ENST00000583535.6 linkuse as main transcript	c.5254G>A	p.Ala1752Thr	missense_variant	36/41	5	NM_002470.4	ENSP00000464317.1		P11055

Frequencies

GnomAD3 genomes

AF:

0.0218

AC:

3317

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0310

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0131

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.00269

Gnomad SAS

AF:

0.0269

Gnomad FIN

AF:

0.0191

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0209

Gnomad OTH

AF:

0.0210

GnomAD3 exomes

AF:

0.0179

AC:

4507

AN:

251184

Hom.:

AF XY:

0.0186

AC XY:

2525

AN XY:

135772

show subpopulations

Gnomad AFR exome

AF:

0.0299

Gnomad AMR exome

AF:

0.00764

Gnomad ASJ exome

AF:

0.00873

Gnomad EAS exome

AF:

0.000870

Gnomad SAS exome

AF:

0.0290

Gnomad FIN exome

AF:

0.0172

Gnomad NFE exome

AF:

0.0201

Gnomad OTH exome

AF:

0.0184

GnomAD4 exome

AF:

0.0202

AC:

29524

AN:

1461856

Hom.:

324

Cov.:

AF XY:

0.0204

AC XY:

14864

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.0284

Gnomad4 AMR exome

AF:

0.00769

Gnomad4 ASJ exome

AF:

0.00838

Gnomad4 EAS exome

AF:

0.00589

Gnomad4 SAS exome

AF:

0.0287

Gnomad4 FIN exome

AF:

0.0165

Gnomad4 NFE exome

AF:

0.0209

Gnomad4 OTH exome

AF:

0.0191

GnomAD4 genome

AF:

0.0218

AC:

3323

AN:

152254

Hom.:

Cov.:

AF XY:

0.0214

AC XY:

1590

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0309

Gnomad4 AMR

AF:

0.0131

Gnomad4 ASJ

AF:

0.00634

Gnomad4 EAS

AF:

0.00270

Gnomad4 SAS

AF:

0.0272

Gnomad4 FIN

AF:

0.0191

Gnomad4 NFE

AF:

0.0209

Gnomad4 OTH

AF:

0.0222

Alfa

AF:

0.0175

Hom.:

Bravo

AF:

0.0209

TwinsUK

AF:

0.0183

AC:

ALSPAC

AF:

0.0223

AC:

ESP6500AA

AF:

0.0293

AC:

129

ESP6500EA

AF:

0.0202

AC:

174

ExAC

AF:

0.0192

AC:

2327

Asia WGS

AF:

0.0360

AC:

125

AN:

3478

EpiCase

AF:

0.0207

EpiControl

AF:

0.0180

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	MYH3: BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2020	This variant is associated with the following publications: (PMID: 29687901, 30967136, 22519952, 32315303) -

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. -

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

0.084

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.63

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0059

MetaSVM

Uncertain

-0.14

MutationAssessor

Uncertain

2.7

PrimateAI

Uncertain

0.62

Sift4G

Benign

0.080

Polyphen

0.29

Vest4

0.16

MPC

0.31

ClinPred

0.017

GERP RS

5.0

Varity_R

0.23

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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