NM_002470.4:c.1504T>G

Variant names:

• chr17-10642903-A-C
• rs797045727
• NM_002470.4:c.1504T>G

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 in the MYH3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 36 curated pathogenic missense variants (we use a threshold of 10). The gene has 26 curated benign missense variants. Gene score misZ: 1.7445 (below the threshold of 3.09). Trascript score misZ: 4.649 (above the threshold of 3.09). GenCC associations: The gene is linked to spondylocarpotarsal synostosis syndrome, contractures, pterygia, and variable skeletal fusions syndrome 1B, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, digitotalar dysmorphism, autosomal recessive multiple pterygium syndrome, Freeman-Sheldon syndrome, distal arthrogryposis type 2B1, Sheldon-hall syndrome.
• 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 rank	MANE	Protein	UniProt
MYH3	NM_002470.4	c.1504T>G	p.Tyr502Asp	missense_variant	Exon 15 of 41	ENST00000583535.6	NP_002461.2
MYH3	XM_011523870.4	c.1504T>G	p.Tyr502Asp	missense_variant	Exon 15 of 41		XP_011522172.1
MYH3	XM_011523871.3	c.1504T>G	p.Tyr502Asp	missense_variant	Exon 15 of 41		XP_011522173.1
MYH3	XM_047436127.1	c.1504T>G	p.Tyr502Asp	missense_variant	Exon 17 of 43		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH3	ENST00000583535.6	c.1504T>G	p.Tyr502Asp	missense_variant	Exon 15 of 41	5	NM_002470.4	ENSP00000464317.1

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

Oct 30, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
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;