17-10642813-T-G

Variant names:

• chr17-10642813-T-G
• rs2285468
• NM_002470.4:c.1581+13A>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002470.4(MYH3):​c.1581+13A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.716 in 1,613,388 control chromosomes in the GnomAD database, including 423,631 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (32086 hom., cov: 31)
  • Exomes 𝑓: 0.72 (391545 hom.)
• Consequence: MYH3 NM_002470.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.895

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 17-10642813-T-G is Benign according to our data. Variant chr17-10642813-T-G is described in ClinVar as [Benign]. Clinvar id is 258671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10642813-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.764 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH3	NM_002470.4	c.1581+13A>C		intron_variant	Intron 15 of 40	ENST00000583535.6	NP_002461.2
MYH3	XM_011523870.4	c.1581+13A>C		intron_variant	Intron 15 of 40		XP_011522172.1
MYH3	XM_011523871.3	c.1581+13A>C		intron_variant	Intron 15 of 40		XP_011522173.1
MYH3	XM_047436127.1	c.1581+13A>C		intron_variant	Intron 17 of 42		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH3	ENST00000583535.6	c.1581+13A>C		intron_variant	Intron 15 of 40	5	NM_002470.4	ENSP00000464317.1

Frequencies

GnomAD3 genomes AF: 0.632 AC: 95718 AN: 151540 Hom.: 32078 Cov.: 31

Gnomad AFR AF: 0.421

Gnomad AMI AF: 0.792

Gnomad AMR AF: 0.590

Gnomad ASJ AF: 0.731

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.592

Gnomad FIN AF: 0.723

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.769

Gnomad OTH AF: 0.633

GnomAD3 exomes AF: 0.648 AC: 162880 AN: 251420 Hom.: 55471 AF XY: 0.660 AC XY: 89642 AN XY: 135894

Gnomad AFR exome AF: 0.419

Gnomad AMR exome AF: 0.485

Gnomad ASJ exome AF: 0.730

Gnomad EAS exome AF: 0.361

Gnomad SAS exome AF: 0.604

Gnomad FIN exome AF: 0.731

Gnomad NFE exome AF: 0.763

Gnomad OTH exome AF: 0.687

GnomAD4 exome AF: 0.725 AC: 1059165 AN: 1461730 Hom.: 391545 Cov.: 120 AF XY: 0.723 AC XY: 525940 AN XY: 727168

Gnomad4 AFR exome AF: 0.405

Gnomad4 AMR exome AF: 0.498

Gnomad4 ASJ exome AF: 0.728

Gnomad4 EAS exome AF: 0.355

Gnomad4 SAS exome AF: 0.604

Gnomad4 FIN exome AF: 0.737

Gnomad4 NFE exome AF: 0.768

Gnomad4 OTH exome AF: 0.694

GnomAD4 genome AF: 0.631 AC: 95751 AN: 151658 Hom.: 32086 Cov.: 31 AF XY: 0.625 AC XY: 46292 AN XY: 74106

Gnomad4 AFR AF: 0.421

Gnomad4 AMR AF: 0.590

Gnomad4 ASJ AF: 0.731

Gnomad4 EAS AF: 0.371

Gnomad4 SAS AF: 0.592

Gnomad4 FIN AF: 0.723

Gnomad4 NFE AF: 0.769

Gnomad4 OTH AF: 0.637

Alfa AF: 0.731 Hom.: 63835

Bravo AF: 0.606

Asia WGS AF: 0.500 AC: 1742 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

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

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 07, 2018

GeneDx

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. -

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

- -

Arthrogryposis, distal, type 2B3 Benign:1

Sep 05, 2021

Genome-Nilou Lab

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.12
DANN	Benign	0.34

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

Other links and lift over

dbSNP: rs2285468; hg19: chr17-10546130; COSMIC: COSV56868340;