rs2285479

Positions:

• chr17-10632701-G-A

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.4731C>T​(p.Ile1577Ile) 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 1,613,692 control chromosomes in the GnomAD database, including 379,821 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (27894 hom., cov: 32)
  • Exomes 𝑓: 0.69 (351927 hom.)
• Consequence: MYH3 NM_002470.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -4.90

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]

LOC124903927 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 17-10632701-G-A is Benign according to our data. Variant chr17-10632701-G-A is described in ClinVar as [Benign]. Clinvar id is 129663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10632701-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.9 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.4731C>T	p.Ile1577Ile	synonymous_variant	34/41	ENST00000583535.6	NP_002461.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH3	ENST00000583535.6	c.4731C>T	p.Ile1577Ile	synonymous_variant	34/41	5	NM_002470.4	ENSP00000464317.1

Frequencies

GnomAD3 genomes AF: 0.575 AC: 87312 AN: 151846 Hom.: 27892 Cov.: 32

Gnomad AFR AF: 0.302

Gnomad AMI AF: 0.746

Gnomad AMR AF: 0.562

Gnomad ASJ AF: 0.703

Gnomad EAS AF: 0.370

Gnomad SAS AF: 0.523

Gnomad FIN AF: 0.707

Gnomad MID AF: 0.548

Gnomad NFE AF: 0.733

Gnomad OTH AF: 0.591

GnomAD3 exomes AF: 0.611 AC: 153517 AN: 251450 Hom.: 49790 AF XY: 0.623 AC XY: 84604 AN XY: 135894

Gnomad AFR exome AF: 0.299

Gnomad AMR exome AF: 0.467

Gnomad ASJ exome AF: 0.708

Gnomad EAS exome AF: 0.362

Gnomad SAS exome AF: 0.540

Gnomad FIN exome AF: 0.714

Gnomad NFE exome AF: 0.727

Gnomad OTH exome AF: 0.652

GnomAD4 exome AF: 0.686 AC: 1002231 AN: 1461728 Hom.: 351927 Cov.: 55 AF XY: 0.684 AC XY: 497622 AN XY: 727170

Gnomad4 AFR exome AF: 0.282

Gnomad4 AMR exome AF: 0.480

Gnomad4 ASJ exome AF: 0.705

Gnomad4 EAS exome AF: 0.367

Gnomad4 SAS exome AF: 0.540

Gnomad4 FIN exome AF: 0.720

Gnomad4 NFE exome AF: 0.729

Gnomad4 OTH exome AF: 0.652

GnomAD4 genome AF: 0.575 AC: 87339 AN: 151964 Hom.: 27894 Cov.: 32 AF XY: 0.570 AC XY: 42322 AN XY: 74270

Gnomad4 AFR AF: 0.301

Gnomad4 AMR AF: 0.562

Gnomad4 ASJ AF: 0.703

Gnomad4 EAS AF: 0.371

Gnomad4 SAS AF: 0.523

Gnomad4 FIN AF: 0.707

Gnomad4 NFE AF: 0.733

Gnomad4 OTH AF: 0.591

Alfa AF: 0.688 Hom.: 46509

Bravo AF: 0.549

Asia WGS AF: 0.449 AC: 1567 AN: 3478

EpiCase AF: 0.729

EpiControl AF: 0.723

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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. -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Arthrogryposis, distal, type 2B3 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	-0.77
CADD	Benign	0.034
DANN	Benign	0.53

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: rs2285479; hg19: chr17-10536018; COSMIC: COSV56862393; COSMIC: COSV56862393;