17-10639154-T-G

Variant names:

• chr17-10639154-T-G
• rs2285475
• NM_002470.4:c.3138A>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002470.4(MYH3):​c.3138A>C​(p.Arg1046Arg) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -6.14
• Publications: 25 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]

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 -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 VariationId is 129656.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002470.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH3	NM_002470.4	MANE Select	c.3138A>C	p.Arg1046Arg	synonymous	Exon 25 of 41	NP_002461.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH3	ENST00000583535.6	TSL:5 MANE Select	c.3138A>C	p.Arg1046Arg	synonymous	Exon 25 of 41	ENSP00000464317.1
	MYHAS	ENST00000579914.2	TSL:4	n.705+25277T>G		intron	N/A
	MYHAS	ENST00000584139.2	TSL:3	n.1041+25277T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.573 AC: 87102 AN: 151978 Hom.: 27825 Cov.: 32

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

GnomAD2 exomes AF: 0.610 AC: 153443 AN: 251460 AF XY: 0.622

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 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.: 65 AF XY: 0.684 AC XY: 497631 AN XY: 727190

African (AFR) AF: 0.277 AC: 9261 AN: 33474

American (AMR) AF: 0.480 AC: 21460 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.705 AC: 18413 AN: 26134

East Asian (EAS) AF: 0.368 AC: 14611 AN: 39700

South Asian (SAS) AF: 0.539 AC: 46511 AN: 86248

European-Finnish (FIN) AF: 0.720 AC: 38466 AN: 53418

Middle Eastern (MID) AF: 0.557 AC: 3211 AN: 5766

European-Non Finnish (NFE) AF: 0.729 AC: 810900 AN: 1111914

Other (OTH) AF: 0.653 AC: 39406 AN: 60392

GnomAD4 genome AF: 0.573 AC: 87135 AN: 152100 Hom.: 27831 Cov.: 32 AF XY: 0.568 AC XY: 42222 AN XY: 74348

African (AFR) AF: 0.295 AC: 12226 AN: 41488

American (AMR) AF: 0.561 AC: 8573 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.703 AC: 2441 AN: 3472

East Asian (EAS) AF: 0.372 AC: 1926 AN: 5176

South Asian (SAS) AF: 0.522 AC: 2514 AN: 4812

European-Finnish (FIN) AF: 0.707 AC: 7478 AN: 10574

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.734 AC: 49887 AN: 67990

Other (OTH) AF: 0.595 AC: 1254 AN: 2108

Alfa AF: 0.685 Hom.: 64939

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:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:3

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Freeman-Sheldon syndrome Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Arthrogryposis, distal, type 2B3 Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Contractures, pterygia, and variable skeletal fusions syndrome 1B Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 11, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

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

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.20
DANN	Benign	0.61
PhyloP100		-6.1
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2285475; hg19: chr17-10542471; COSMIC: COSV56861471;