chr5-129461279-GC-G

Position:

• chr5-129461279-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_133638.6(ADAMTS19):​c.270delC​(p.Ser91fs) variant causes a frameshift 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 (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADAMTS19 NM_133638.6 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.626

Genes affected

ADAMTS19 (HGNC:17111): (ADAM metallopeptidase with thrombospondin type 1 motif 19) This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motif) protein family. Members of the family share several distinct protein modules, including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. Individual members of this family differ in the number of C-terminal TS motifs, and some have unique C-terminal domains. The protein encoded by this gene has high sequence similarity to the protein encoded by ADAMTS16, another family member. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-129461279-GC-G is Pathogenic according to our data. Variant chr5-129461279-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 2050921.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS19	NM_133638.6	c.270delC	p.Ser91fs	frameshift_variant	2/23	ENST00000274487.9	NP_598377.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS19	ENST00000274487.9	c.270delC	p.Ser91fs	frameshift_variant	2/23	1	NM_133638.6	ENSP00000274487.5
ADAMTS19	ENST00000505791.5	n.91+798delC		intron_variant		3		ENSP00000423537.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 27, 2022

This sequence change creates a premature translational stop signal (p.Ser85Leufs*159) in the ADAMTS19 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ADAMTS19 are known to be pathogenic (PMID: 31844321, 32323311). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ADAMTS19-related conditions. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-128796972;