NM_002470.4:c.1123G>A

Variant names:

• chr17-10645725-C-T
• rs121913621
• NM_002470.4:c.1123G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_002470.4(MYH3):​c.1123G>A​(p.Glu375Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 30)
• Consequence: MYH3 NM_002470.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:2
• Conservation: PhyloP100: 7.91
• Publications: 9 publications found

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]

MYHAS (HGNC:50609): (myosin heavy chain gene cluster antisense RNA) Predicted to enable primary miRNA binding activity. Predicted to be involved in response to muscle activity and skeletal muscle fiber development. Predicted to act upstream of or within with a positive effect on gene expression. Predicted to be located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 17-10645725-C-T is Pathogenic according to our data. Variant chr17-10645725-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 14143.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH3	NM_002470.4	c.1123G>A	p.Glu375Lys	missense_variant	Exon 12 of 41	ENST00000583535.6	NP_002461.2
MYH3	XM_011523870.4	c.1123G>A	p.Glu375Lys	missense_variant	Exon 12 of 41		XP_011522172.1
MYH3	XM_011523871.3	c.1123G>A	p.Glu375Lys	missense_variant	Exon 12 of 41		XP_011522173.1
MYH3	XM_047436127.1	c.1123G>A	p.Glu375Lys	missense_variant	Exon 14 of 43		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH3	ENST00000583535.6	c.1123G>A	p.Glu375Lys	missense_variant	Exon 12 of 41	5	NM_002470.4	ENSP00000464317.1
MYHAS	ENST00000579914.2	n.705+31848C>T		intron_variant	Intron 4 of 4	4
MYHAS	ENST00000584139.2	n.1041+31848C>T		intron_variant	Intron 7 of 8	3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 63

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Nov 06, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31030430, 19309503, 29625835, 17380469, 16642020, 38421226, 26578207) -

Jun 07, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 14143). This missense change has been observed in individuals with distal arthrogryposis (PMID: 16642020, 26578207, 31030430). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 375 of the MYH3 protein (p.Glu375Lys). -

Feb 26, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arthrogryposis, distal, type 2B3 Pathogenic:2 Uncertain:1

Jun 19, 2024

Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM1_moderate;PM2_supporting;PP3_supporting;PP4_supporting -

May 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 21, 2019

SIB Swiss Institute of Bioinformatics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as a variant of uncertain significance for Arthrogryposis, distal, 2B3, autosomal dominant. The following ACMG Tag(s) were applied: PM2, PP3, PM1. -

MYH3-related disorder Pathogenic:1

Oct 06, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MYH3 c.1123G>A variant is predicted to result in the amino acid substitution p.Glu375Lys. This variant has been reported in the heterozygous state in at least one family with distal arthrogryposis (reported as 1192G>A, p.Glu375Lys in Toydemir et al. 2006. PubMed ID: 16642020). At PreventionGenetics, we have observed this variant in the heterozygous state in additional individuals with distal arthrogryposis (Internal Data, PreventionGenetics). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic for autosomal dominant distal arthrogryposis. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.87	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.99	D
Vest4		0.90
MutPred		0.86		Gain of ubiquitination at E375 (P = 0.0051);
MVP		0.86
MPC		2.0
ClinPred		0.98	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.65
Mutation Taster		=4/96	disease causing

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

Other links and lift over

dbSNP: rs121913621; hg19: chr17-10549042; COSMIC: COSV56862372; COSMIC: COSV56862372;