rs201626

chr17-10638424-A-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.3348T>C(p.Ile1116=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,599,252 control chromosomes in the GnomAD database, including 20,966 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2539 hom., cov: 30)
  • Exomes 𝑓: 0.12 (18427 hom.)
• Consequence: MYH3 NM_002470.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.54

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=-0.83).
• BP6: Variant 17-10638424-A-G is Benign according to our data. Variant chr17-10638424-A-G is described in ClinVar as [Benign]. Clinvar id is 129657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10638424-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.54 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.586 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH3	NM_002470.4	c.3348T>C	p.Ile1116=	synonymous_variant	27/41	ENST00000583535.6
MYH3	XM_011523870.4	c.3348T>C	p.Ile1116=	synonymous_variant	27/41
MYH3	XM_011523871.3	c.3348T>C	p.Ile1116=	synonymous_variant	27/41
MYH3	XM_047436127.1	c.3348T>C	p.Ile1116=	synonymous_variant	29/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH3	ENST00000583535.6	c.3348T>C	p.Ile1116=	synonymous_variant	27/41	5	NM_002470.4	P1

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22686 AN: 151524 Hom.: 2547 Cov.: 30

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.0912

Gnomad AMR AF: 0.251

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.605

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.0874

Gnomad OTH AF: 0.169

GnomAD3 exomes AF: 0.199 AC: 47042 AN: 236198 Hom.: 7554 AF XY: 0.190 AC XY: 24625 AN XY: 129398

Gnomad AFR exome AF: 0.144

Gnomad AMR exome AF: 0.364

Gnomad ASJ exome AF: 0.169

Gnomad EAS exome AF: 0.614

Gnomad SAS exome AF: 0.228

Gnomad FIN exome AF: 0.137

Gnomad NFE exome AF: 0.0917

Gnomad OTH exome AF: 0.171

GnomAD4 exome AF: 0.122 AC: 176203 AN: 1447612 Hom.: 18427 Cov.: 38 AF XY: 0.124 AC XY: 89293 AN XY: 720532

Gnomad4 AFR exome AF: 0.152

Gnomad4 AMR exome AF: 0.350

Gnomad4 ASJ exome AF: 0.168

Gnomad4 EAS exome AF: 0.602

Gnomad4 SAS exome AF: 0.231

Gnomad4 FIN exome AF: 0.131

Gnomad4 NFE exome AF: 0.0829

Gnomad4 OTH exome AF: 0.149

GnomAD4 genome AF: 0.150 AC: 22694 AN: 151640 Hom.: 2539 Cov.: 30 AF XY: 0.159 AC XY: 11754 AN XY: 74054

Gnomad4 AFR AF: 0.147

Gnomad4 AMR AF: 0.251

Gnomad4 ASJ AF: 0.184

Gnomad4 EAS AF: 0.604

Gnomad4 SAS AF: 0.246

Gnomad4 FIN AF: 0.141

Gnomad4 NFE AF: 0.0875

Gnomad4 OTH AF: 0.167

Alfa AF: 0.118 Hom.: 1495

Bravo AF: 0.163

Asia WGS AF: 0.373 AC: 1292 AN: 3478

EpiCase AF: 0.0951

EpiControl AF: 0.101

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 02, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Freeman-Sheldon syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	1.3
Dann	Benign	0.51

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: rs201626; hg19: chr17-10541741; COSMIC: COSV56860805;