rs2285477

chr17-10638198-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_002470.4(MYH3):c.3574G>A(p.Ala1192Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.749 in 1,613,298 control chromosomes in the GnomAD database, including 460,038 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1192M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.69 (37317 hom., cov: 27)
  • Exomes 𝑓: 0.75 (422721 hom.)
• Consequence: MYH3 NM_002470.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.761

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYH3
• BP4: Computational evidence support a benign effect (MetaRNN=8.30933E-6).
• BP6: Variant 17-10638198-C-T is Benign according to our data. Variant chr17-10638198-C-T is described in ClinVar as [Benign]. Clinvar id is 129658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10638198-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.79 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH3	NM_002470.4	c.3574G>A	p.Ala1192Thr	missense_variant	27/41	ENST00000583535.6
MYH3	XM_011523870.4	c.3574G>A	p.Ala1192Thr	missense_variant	27/41
MYH3	XM_011523871.3	c.3574G>A	p.Ala1192Thr	missense_variant	27/41
MYH3	XM_047436127.1	c.3574G>A	p.Ala1192Thr	missense_variant	29/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH3	ENST00000583535.6	c.3574G>A	p.Ala1192Thr	missense_variant	27/41	5	NM_002470.4	P1

Frequencies

GnomAD3 genomes AF: 0.693 AC: 104795 AN: 151322 Hom.: 37289 Cov.: 27

Gnomad AFR AF: 0.567

Gnomad AMI AF: 0.793

Gnomad AMR AF: 0.648

Gnomad ASJ AF: 0.752

Gnomad EAS AF: 0.380

Gnomad SAS AF: 0.613

Gnomad FIN AF: 0.742

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.796

Gnomad OTH AF: 0.689

GnomAD3 exomes AF: 0.687 AC: 172652 AN: 251444 Hom.: 61461 AF XY: 0.695 AC XY: 94404 AN XY: 135896

Gnomad AFR exome AF: 0.568

Gnomad AMR exome AF: 0.556

Gnomad ASJ exome AF: 0.755

Gnomad EAS exome AF: 0.374

Gnomad SAS exome AF: 0.631

Gnomad FIN exome AF: 0.749

Gnomad NFE exome AF: 0.789

Gnomad OTH exome AF: 0.719

GnomAD4 exome AF: 0.755 AC: 1103404 AN: 1461860 Hom.: 422721 Cov.: 109 AF XY: 0.753 AC XY: 547392 AN XY: 727230

Gnomad4 AFR exome AF: 0.553

Gnomad4 AMR exome AF: 0.568

Gnomad4 ASJ exome AF: 0.753

Gnomad4 EAS exome AF: 0.382

Gnomad4 SAS exome AF: 0.630

Gnomad4 FIN exome AF: 0.754

Gnomad4 NFE exome AF: 0.794

Gnomad4 OTH exome AF: 0.728

GnomAD4 genome AF: 0.693 AC: 104876 AN: 151438 Hom.: 37317 Cov.: 27 AF XY: 0.685 AC XY: 50617 AN XY: 73936

Gnomad4 AFR AF: 0.567

Gnomad4 AMR AF: 0.648

Gnomad4 ASJ AF: 0.752

Gnomad4 EAS AF: 0.381

Gnomad4 SAS AF: 0.612

Gnomad4 FIN AF: 0.742

Gnomad4 NFE AF: 0.796

Gnomad4 OTH AF: 0.694

Alfa AF: 0.752 Hom.: 68998

Bravo AF: 0.676

TwinsUK AF: 0.804 AC: 2981

ALSPAC AF: 0.791 AC: 3048

ESP6500AA AF: 0.574 AC: 2529

ESP6500EA AF: 0.789 AC: 6787

ExAC AF: 0.690 AC: 83758

Asia WGS AF: 0.545 AC: 1901 AN: 3478

EpiCase AF: 0.789

EpiControl AF: 0.782

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	-	- -

Freeman-Sheldon syndrome Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 05, 2019	This variant is associated with the following publications: (PMID: 32315303) -
Benign, criteria provided, single submitter	clinical testing	Invitae	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
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	2.2
Dann	Benign	0.97
DEOGEN2	Benign	0.30	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0000083	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.95	L
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.31	T
Sift4G	Benign	0.52	T
Polyphen		0.014	B
Vest4		0.0080
MPC		0.25
ClinPred		0.0016	T
GERP RS		-2.1
Varity_R		0.027
gMVP		0.15

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: rs2285477; hg19: chr17-10541515; COSMIC: COSV56862237;