chr17-10631643-C-T

Variant names:

• chr17-10631643-C-T
• rs34393601
• NM_002470.4:c.5254G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1752S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.022 (34 hom., cov: 32)
  • Exomes 𝑓: 0.020 (324 hom.)
• Consequence: MYH3 NM_002470.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 4.88
• Publications: 12 publications found

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]

LOC124903927 (HGNC:):

MYHAS (HGNC:50609): (myosin heavy chain gene cluster antisense RNA) Predicted to enable primary miRNA binding activity. Predicted to be involved in response to muscle activity and skeletal muscle fiber development. Predicted to act upstream of or within with a positive effect on gene expression. Predicted to be located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• 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.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 34 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH3	NM_002470.4	c.5254G>A	p.Ala1752Thr	missense_variant	Exon 36 of 41	ENST00000583535.6	NP_002461.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH3	ENST00000583535.6	c.5254G>A	p.Ala1752Thr	missense_variant	Exon 36 of 41	5	NM_002470.4	ENSP00000464317.1
MYHAS	ENST00000579914.2	n.705+17766C>T		intron_variant	Intron 4 of 4	4
MYHAS	ENST00000584139.2	n.1041+17766C>T		intron_variant	Intron 7 of 8	3
MYHAS	ENST00000781814.1	n.165-3042C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.0218 AC: 3317 AN: 152136 Hom.: 34 Cov.: 32

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

GnomAD2 exomes AF: 0.0179 AC: 4507 AN: 251184 AF XY: 0.0186

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 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.: 32 AF XY: 0.0204 AC XY: 14864 AN XY: 727226

African (AFR) AF: 0.0284 AC: 951 AN: 33478

American (AMR) AF: 0.00769 AC: 344 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00838 AC: 219 AN: 26136

East Asian (EAS) AF: 0.00589 AC: 234 AN: 39700

South Asian (SAS) AF: 0.0287 AC: 2473 AN: 86246

European-Finnish (FIN) AF: 0.0165 AC: 883 AN: 53420

Middle Eastern (MID) AF: 0.00745 AC: 43 AN: 5768

European-Non Finnish (NFE) AF: 0.0209 AC: 23221 AN: 1111994

Other (OTH) AF: 0.0191 AC: 1156 AN: 60394

GnomAD4 genome AF: 0.0218 AC: 3323 AN: 152254 Hom.: 34 Cov.: 32 AF XY: 0.0214 AC XY: 1590 AN XY: 74450

African (AFR) AF: 0.0309 AC: 1284 AN: 41542

American (AMR) AF: 0.0131 AC: 200 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3468

East Asian (EAS) AF: 0.00270 AC: 14 AN: 5186

South Asian (SAS) AF: 0.0272 AC: 131 AN: 4822

European-Finnish (FIN) AF: 0.0191 AC: 203 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0209 AC: 1422 AN: 68008

Other (OTH) AF: 0.0222 AC: 47 AN: 2116

Alfa AF: 0.0196 Hom.: 105

Bravo AF: 0.0209

TwinsUK AF: 0.0183 AC: 68

ALSPAC AF: 0.0223 AC: 86

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

Submissions by phenotype

not provided Benign:5

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYH3: BS1, BS2 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29687901, 30967136, 22519952, 32315303) -

not specified Benign:3

-

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. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Freeman-Sheldon syndrome Benign:1

Jan 12, 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 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0059	T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		4.9
PrimateAI	Uncertain	0.62	T
Sift4G	Benign	0.080	T
Polyphen		0.29	B
Vest4		0.16
MPC		0.31
ClinPred		0.017	T
GERP RS		5.0
Varity_R		0.23
gMVP		0.80
Mutation Taster		=94/6	polymorphism (auto)

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

Other links and lift over

dbSNP: rs34393601; hg19: chr17-10534960; COSMIC: COSV56868109; COSMIC: COSV56868109;