9-133537223-T-A

Position:

• chr9-133537223-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014694.4(ADAMTSL2):​c.91-182T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 151,940 control chromosomes in the GnomAD database, including 7,842 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.30 (7842 hom., cov: 33)
• Consequence: ADAMTSL2 NM_014694.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.44

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 9-133537223-T-A is Benign according to our data. Variant chr9-133537223-T-A is described in ClinVar as [Benign]. Clinvar id is 680523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.473 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTSL2	NM_014694.4	c.91-182T>A		intron_variant		ENST00000651351.2	NP_055509.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTSL2	ENST00000651351.2	c.91-182T>A		intron_variant			NM_014694.4	ENSP00000498961	P1
ADAMTSL2	ENST00000354484.8	c.91-182T>A		intron_variant		1		ENSP00000346478	P1
ADAMTSL2	ENST00000393060.1	c.91-182T>A		intron_variant		1		ENSP00000376780	P1
ADAMTSL2	ENST00000393061.7	c.418-182T>A		intron_variant		1		ENSP00000376781

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46275 AN: 151822 Hom.: 7836 Cov.: 33

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.433

Gnomad AMR AF: 0.217

Gnomad ASJ AF: 0.353

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.489

Gnomad FIN AF: 0.444

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.348

Gnomad OTH AF: 0.286

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

GnomAD4 genome AF: 0.305 AC: 46306 AN: 151940 Hom.: 7842 Cov.: 33 AF XY: 0.311 AC XY: 23123 AN XY: 74276

Gnomad4 AFR AF: 0.187

Gnomad4 AMR AF: 0.217

Gnomad4 ASJ AF: 0.353

Gnomad4 EAS AF: 0.431

Gnomad4 SAS AF: 0.489

Gnomad4 FIN AF: 0.444

Gnomad4 NFE AF: 0.348

Gnomad4 OTH AF: 0.292

Alfa AF: 0.225 Hom.: 631

Bravo AF: 0.274

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.019
DANN	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs11516156; hg19: chr9-136402345;