rs121913622

chr17-10644376-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_002470.4(MYH3):c.1385A>G(p.Asp462Gly) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYH3 NM_002470.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 8.02

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MYH3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH3	NM_002470.4	c.1385A>G	p.Asp462Gly	missense_variant	14/41	ENST00000583535.6
MYH3	XM_011523870.4	c.1385A>G	p.Asp462Gly	missense_variant	14/41
MYH3	XM_011523871.3	c.1385A>G	p.Asp462Gly	missense_variant	14/41
MYH3	XM_047436127.1	c.1385A>G	p.Asp462Gly	missense_variant	16/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH3	ENST00000583535.6	c.1385A>G	p.Asp462Gly	missense_variant	14/41	5	NM_002470.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Aug 21, 2019	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2008	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	5.0	H
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.86	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		1.0
MutPred		0.95		Loss of catalytic residue at D462 (P = 0.0071);
MVP		0.92
MPC		2.2
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.96
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121913622; hg19: chr17-10547693;