chr17-10641341-CTTAAA-C

Position:

• chr17-10641341-CTTAAA-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 9P and 1B. PVS1 PP5 BS2_Supporting

The NM_002470.4(MYH3):​c.1986_1990del​(p.Asn662LysfsTer15) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,030 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: MYH3 NM_002470.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 9.30

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.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 17-10641341-CTTAAA-C is Pathogenic according to our data. Variant chr17-10641341-CTTAAA-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 503890.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}. Variant chr17-10641341-CTTAAA-C is described in Lovd as [Likely_pathogenic].
• BS2: High AC in GnomAdExome4 at 19 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH3	NM_002470.4	c.1986_1990del	p.Asn662LysfsTer15	frameshift_variant	18/41	ENST00000583535.6	NP_002461.2
MYH3	XM_011523870.4	c.1986_1990del	p.Asn662LysfsTer15	frameshift_variant	18/41		XP_011522172.1
MYH3	XM_011523871.3	c.1986_1990del	p.Asn662LysfsTer15	frameshift_variant	18/41		XP_011522173.1
MYH3	XM_047436127.1	c.1986_1990del	p.Asn662LysfsTer15	frameshift_variant	20/43		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH3	ENST00000583535.6	c.1986_1990del	p.Asn662LysfsTer15	frameshift_variant	18/41	5	NM_002470.4	ENSP00000464317	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251478 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461030 Hom.: 0 AF XY: 0.0000110 AC XY: 8 AN XY: 726914

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Spondylocarpotarsal synostosis syndrome;C1867440:Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genetics Group, University of Otago

Apr 09, 2018

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 03, 2020

Observed as heterozygous variant in individual with spondylocarpotarsal synostosis syndrome; a second variant in MYH3 was not identified through whole exome sequencing, however whole genome sequencing was not available at the time of publication (Cameron-Christie et al., 2018); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29805041) -

Contractures, pterygia, and variable skeletal fusions syndrome 1B Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Provincial Medical Genetics Program of British Columbia, University of British Columbia

Jan 01, 2022

- -

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: rs771300756; hg19: chr17-10544658;