rs878853126

Positions:

• chr17-10639075-C-CATT

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP5

The NM_002470.4(MYH3):​c.3214_3216dupAAT​(p.Asn1072dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYH3 NM_002470.4 conservative_inframe_insertion
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 0.163

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_002470.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 17-10639075-C-CATT is Pathogenic according to our data. Variant chr17-10639075-C-CATT is described in ClinVar as [Pathogenic]. Clinvar id is 235829.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH3	NM_002470.4	c.3214_3216dupAAT	p.Asn1072dup	conservative_inframe_insertion	25/41	ENST00000583535.6	NP_002461.2
MYH3	XM_011523870.4	c.3214_3216dupAAT	p.Asn1072dup	conservative_inframe_insertion	25/41		XP_011522172.1
MYH3	XM_011523871.3	c.3214_3216dupAAT	p.Asn1072dup	conservative_inframe_insertion	25/41		XP_011522173.1
MYH3	XM_047436127.1	c.3214_3216dupAAT	p.Asn1072dup	conservative_inframe_insertion	27/43		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH3	ENST00000583535.6	c.3214_3216dupAAT	p.Asn1072dup	conservative_inframe_insertion	25/41	5	NM_002470.4	ENSP00000464317.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	May 07, 2015	- -
Pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	May 19, 2015	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs878853126; hg19: chr17-10542392;