rs797045727

Positions:

• chr17-10642903-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_002470.4(MYH3):​c.1504T>G​(p.Tyr502Asp) 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 Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH3 NM_002470.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.32

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 8 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, 0.971
• PP5: Variant 17-10642903-A-C is Pathogenic according to our data. Variant chr17-10642903-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 211550.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH3	NM_002470.4	c.1504T>G	p.Tyr502Asp	missense_variant	15/41	ENST00000583535.6
MYH3	XM_011523870.4	c.1504T>G	p.Tyr502Asp	missense_variant	15/41
MYH3	XM_011523871.3	c.1504T>G	p.Tyr502Asp	missense_variant	15/41
MYH3	XM_047436127.1	c.1504T>G	p.Tyr502Asp	missense_variant	17/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH3	ENST00000583535.6	c.1504T>G	p.Tyr502Asp	missense_variant	15/41	5	NM_002470.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Freeman-Sheldon syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 30, 2015

DNA sequence analysis of the MYH3 gene demonstrated a sequence change, c.1504T>G, in exon 15 that results in an amino acid change, p.Tyr502Asp. The p.Tyr502Asp change affects a highly conserved amino acid residue located in a domain of the MYH3 protein that is known to be functional. The p.Tyr502Asp substitution appears to be deleterious/possibly damaging using several in-silico pathogenicity prediction tools (SIFT PolyPhen2, Align GVGD, MutationTaster). This particular amino acid change does not appear to have been described in the literature in other patients with MYH3-related disorders or as a benign sequence change in the MYH3 gene. The p.Tyr502Asp amino acid change occurs in a region of the MYH3 gene where other missense sequence changes have been described in patients with MYH3-related distal. arthrogryposis. To date, the vast majority of pathogenic variants described in the MYH3 gene have been missense. In addition, this variant was found to be present in the de novo state in the patient tested in our laboratory. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.9	H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.92	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.83		Gain of disorder (P = 0.0391);
MVP		0.90
MPC		2.5
ClinPred		0.98	D
GERP RS		4.6
Varity_R		0.96
gMVP		0.99

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: rs797045727; hg19: chr17-10546220;