9-133537468-GAGTGGACCA-G

Variant names:

• chr9-133537468-GAGTGGACCA-G
• NM_014694.4:c.162_170delCAAGTGGAC

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM4 PP3

The NM_014694.4(ADAMTSL2):​c.162_170delCAAGTGGAC​(p.Lys55_Thr57del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADAMTSL2 NM_014694.4 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.53

Genes affected

ADAMTSL2 (HGNC:14631): (ADAMTS like 2) This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) and ADAMTS-like 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 lacks the protease domain, and is therefore of a member of the the ADAMTS-like protein subfamily. It is a secreted glycoprotein that binds the cell surface and extracellular matrix; it also interacts with latent transforming growth factor beta binding protein 1. Mutations in this gene have been associated with geleophysic dysplasia. [provided by RefSeq, Feb 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a domain TSP type-1 1 (size 59) in uniprot entity ATL2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_014694.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_014694.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTSL2	NM_014694.4	c.162_170delCAAGTGGAC	p.Lys55_Thr57del	disruptive_inframe_deletion	Exon 3 of 19	ENST00000651351.2	NP_055509.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTSL2	ENST00000651351.2	c.162_170delCAAGTGGAC	p.Lys55_Thr57del	disruptive_inframe_deletion	Exon 3 of 19		NM_014694.4	ENSP00000498961.2
ADAMTSL2	ENST00000393061.7	c.489_497delCAAGTGGAC	p.Lys164_Thr166del	disruptive_inframe_deletion	Exon 3 of 19	1		ENSP00000376781.3
ADAMTSL2	ENST00000354484.8	c.162_170delCAAGTGGAC	p.Lys55_Thr57del	disruptive_inframe_deletion	Exon 3 of 19	1		ENSP00000346478.4
ADAMTSL2	ENST00000393060.1	c.162_170delCAAGTGGAC	p.Lys55_Thr57del	disruptive_inframe_deletion	Exon 3 of 19	1		ENSP00000376780.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 20, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 3 amino acids in a non-repeat region; In silico analysis supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Splicing

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: chr9-136402590;