9-133536303-G-A

Position:

• chr9-133536303-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_014694.4(ADAMTSL2):​c.-150-260G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.321 in 152,122 control chromosomes in the GnomAD database, including 8,374 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.32 (8374 hom., cov: 33)
• Consequence: ADAMTSL2 NM_014694.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.78

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 9-133536303-G-A is Benign according to our data. Variant chr9-133536303-G-A is described in ClinVar as [Benign]. Clinvar id is 680522.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.457 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTSL2	NM_014694.4	c.-150-260G>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.-150-260G>A		intron_variant			NM_014694.4	ENSP00000498961	P1
ADAMTSL2	ENST00000354484.8	c.-150-260G>A		intron_variant		1		ENSP00000346478	P1
ADAMTSL2	ENST00000393060.1	c.-150-260G>A		intron_variant		1		ENSP00000376780	P1
ADAMTSL2	ENST00000393061.7	c.178-260G>A		intron_variant		1		ENSP00000376781

Frequencies

GnomAD3 genomes AF: 0.321 AC: 48770 AN: 152004 Hom.: 8364 Cov.: 33

Gnomad AFR AF: 0.242

Gnomad AMI AF: 0.431

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.352

Gnomad EAS AF: 0.424

Gnomad SAS AF: 0.472

Gnomad FIN AF: 0.442

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.350

Gnomad OTH AF: 0.295

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

GnomAD4 genome AF: 0.321 AC: 48820 AN: 152122 Hom.: 8374 Cov.: 33 AF XY: 0.327 AC XY: 24315 AN XY: 74376

Gnomad4 AFR AF: 0.243

Gnomad4 AMR AF: 0.225

Gnomad4 ASJ AF: 0.352

Gnomad4 EAS AF: 0.424

Gnomad4 SAS AF: 0.473

Gnomad4 FIN AF: 0.442

Gnomad4 NFE AF: 0.350

Gnomad4 OTH AF: 0.300

Alfa AF: 0.345 Hom.: 1898

Bravo AF: 0.293

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.48
DANN	Benign	0.45

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: rs11525182; hg19: chr9-136401425; COSMIC: COSV63206524;