rs2285469

Positions:

• chr17-10640146-T-C

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.2532A>G​(p.Ala844=) 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 379,839 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (27823 hom., cov: 32)
  • Exomes 𝑓: 0.69 (352016 hom.)
• Consequence: MYH3 NM_002470.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -11.4

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=-0.97).
• BP6: Variant 17-10640146-T-C is Benign according to our data. Variant chr17-10640146-T-C is described in ClinVar as [Benign]. Clinvar id is 129650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10640146-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-11.4 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.728 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH3	NM_002470.4	c.2532A>G	p.Ala844=	synonymous_variant	22/41	ENST00000583535.6	NP_002461.2
MYH3	XM_011523870.4	c.2532A>G	p.Ala844=	synonymous_variant	22/41		XP_011522172.1
MYH3	XM_011523871.3	c.2532A>G	p.Ala844=	synonymous_variant	22/41		XP_011522173.1
MYH3	XM_047436127.1	c.2532A>G	p.Ala844=	synonymous_variant	24/43		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH3	ENST00000583535.6	c.2532A>G	p.Ala844=	synonymous_variant	22/41	5	NM_002470.4	ENSP00000464317	P1

Frequencies

GnomAD3 genomes AF: 0.573 AC: 87069 AN: 151896 Hom.: 27817 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

GnomAD3 exomes AF: 0.610 AC: 153466 AN: 251490 Hom.: 49788 AF XY: 0.622 AC XY: 84587 AN XY: 135920

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 SAS exome AF: 0.538

Gnomad FIN exome AF: 0.715

Gnomad NFE exome AF: 0.728

Gnomad OTH exome AF: 0.652

GnomAD4 exome AF: 0.686 AC: 1002301 AN: 1461856 Hom.: 352016 Cov.: 82 AF XY: 0.684 AC XY: 497675 AN XY: 727234

Gnomad4 AFR exome AF: 0.277

Gnomad4 AMR exome AF: 0.480

Gnomad4 ASJ exome AF: 0.705

Gnomad4 EAS exome AF: 0.368

Gnomad4 SAS exome AF: 0.539

Gnomad4 FIN exome AF: 0.720

Gnomad4 NFE exome AF: 0.729

Gnomad4 OTH exome AF: 0.652

GnomAD4 genome AF: 0.573 AC: 87102 AN: 152014 Hom.: 27823 Cov.: 32 AF XY: 0.568 AC XY: 42214 AN XY: 74306

Gnomad4 AFR AF: 0.295

Gnomad4 AMR AF: 0.561

Gnomad4 ASJ AF: 0.703

Gnomad4 EAS AF: 0.372

Gnomad4 SAS AF: 0.523

Gnomad4 FIN AF: 0.707

Gnomad4 NFE AF: 0.734

Gnomad4 OTH AF: 0.595

Alfa AF: 0.668 Hom.: 16861

Bravo AF: 0.547

Asia WGS AF: 0.465 AC: 1623 AN: 3478

EpiCase AF: 0.730

EpiControl AF: 0.724

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 18, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Freeman-Sheldon syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Arthrogryposis, distal, type 2B3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Distal arthrogryposis type 2B1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.0020
DANN	Benign	0.32

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: rs2285469; hg19: chr17-10543463; COSMIC: COSV56862450;