rs56163389

Variant names:

• chr17-10640068-T-C
• rs56163389
• NM_002470.4:c.2610A>G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002470.4(MYH3):​c.2610A>G​(p.Lys870Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0415 in 1,614,096 control chromosomes in the GnomAD database, including 1,895 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (401 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1494 hom.)
• Consequence: MYH3 NM_002470.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.978

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 17-10640068-T-C is Benign according to our data. Variant chr17-10640068-T-C is described in ClinVar as [Benign]. Clinvar id is 129651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10640068-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.978 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH3	NM_002470.4	c.2610A>G	p.Lys870Lys	synonymous_variant	Exon 22 of 41	ENST00000583535.6	NP_002461.2
MYH3	XM_011523870.4	c.2610A>G	p.Lys870Lys	synonymous_variant	Exon 22 of 41		XP_011522172.1
MYH3	XM_011523871.3	c.2610A>G	p.Lys870Lys	synonymous_variant	Exon 22 of 41		XP_011522173.1
MYH3	XM_047436127.1	c.2610A>G	p.Lys870Lys	synonymous_variant	Exon 24 of 43		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH3	ENST00000583535.6	c.2610A>G	p.Lys870Lys	synonymous_variant	Exon 22 of 41	5	NM_002470.4	ENSP00000464317.1

Frequencies

GnomAD3 genomes AF: 0.0583 AC: 8870 AN: 152098 Hom.: 401 Cov.: 32

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0276

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.00886

Gnomad SAS AF: 0.0699

Gnomad FIN AF: 0.0138

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0355

Gnomad OTH AF: 0.0431

GnomAD3 exomes AF: 0.0388 AC: 9757 AN: 251492 Hom.: 327 AF XY: 0.0383 AC XY: 5209 AN XY: 135918

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.0180

Gnomad ASJ exome AF: 0.0240

Gnomad EAS exome AF: 0.0105

Gnomad SAS exome AF: 0.0664

Gnomad FIN exome AF: 0.0161

Gnomad NFE exome AF: 0.0352

Gnomad OTH exome AF: 0.0354

GnomAD4 exome AF: 0.0398 AC: 58140 AN: 1461880 Hom.: 1494 Cov.: 70 AF XY: 0.0397 AC XY: 28865 AN XY: 727242

Gnomad4 AFR exome AF: 0.132

Gnomad4 AMR exome AF: 0.0183

Gnomad4 ASJ exome AF: 0.0246

Gnomad4 EAS exome AF: 0.00952

Gnomad4 SAS exome AF: 0.0650

Gnomad4 FIN exome AF: 0.0171

Gnomad4 NFE exome AF: 0.0382

Gnomad4 OTH exome AF: 0.0430

GnomAD4 genome AF: 0.0583 AC: 8873 AN: 152216 Hom.: 401 Cov.: 32 AF XY: 0.0563 AC XY: 4194 AN XY: 74438

Gnomad4 AFR AF: 0.127

Gnomad4 AMR AF: 0.0276

Gnomad4 ASJ AF: 0.0291

Gnomad4 EAS AF: 0.00888

Gnomad4 SAS AF: 0.0702

Gnomad4 FIN AF: 0.0138

Gnomad4 NFE AF: 0.0354

Gnomad4 OTH AF: 0.0431

Alfa AF: 0.0444 Hom.: 115

Bravo AF: 0.0602

Asia WGS AF: 0.0390 AC: 134 AN: 3478

EpiCase AF: 0.0317

EpiControl AF: 0.0331

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

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

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

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. -

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 26, 2019

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

- -

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

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
BayesDel_noAF	Benign	-0.71
CADD	Benign	3.1
DANN	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs56163389; hg19: chr17-10543385;