rs878853126

Variant names:

• chr17-10639075-C-CATT
• rs878853126
• NM_002470.4:c.3214_3216dupAAT

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 1 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: Uncertain_significance. The variant received 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 rank	MANE	Protein	UniProt
MYH3	NM_002470.4	c.3214_3216dupAAT	p.Asn1072dup	conservative_inframe_insertion	Exon 25 of 41	ENST00000583535.6	NP_002461.2
MYH3	XM_011523870.4	c.3214_3216dupAAT	p.Asn1072dup	conservative_inframe_insertion	Exon 25 of 41		XP_011522172.1
MYH3	XM_011523871.3	c.3214_3216dupAAT	p.Asn1072dup	conservative_inframe_insertion	Exon 25 of 41		XP_011522173.1
MYH3	XM_047436127.1	c.3214_3216dupAAT	p.Asn1072dup	conservative_inframe_insertion	Exon 27 of 43		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH3	ENST00000583535.6	c.3214_3216dupAAT	p.Asn1072dup	conservative_inframe_insertion	Exon 25 of 41	5	NM_002470.4	ENSP00000464317.1
MYHAS	ENST00000579914.2	n.705+25199_705+25201dupATT		intron_variant	Intron 4 of 4	4
MYHAS	ENST00000584139.2	n.1041+25199_1041+25201dupATT		intron_variant	Intron 7 of 8	3

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

May 07, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 19, 2015

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.16
Mutation Taster		=69/31	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs878853126; hg19: chr17-10542392;