9-133536484-A-C

Position:

• chr9-133536484-A-C

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.-150-79A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.601 in 1,476,806 control chromosomes in the GnomAD database, including 268,778 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (27492 hom., cov: 34)
  • Exomes 𝑓: 0.60 (241286 hom.)
• Consequence: ADAMTSL2 NM_014694.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.16

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=-0.91).
• BP6: Variant 9-133536484-A-C is Benign according to our data. Variant chr9-133536484-A-C is described in ClinVar as [Benign]. Clinvar id is 680461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.609 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTSL2	NM_014694.4	c.-150-79A>C		intron_variant		ENST00000651351.2	NP_055509.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTSL2	ENST00000651351.2	c.-150-79A>C		intron_variant			NM_014694.4	ENSP00000498961	P1
ADAMTSL2	ENST00000354484.8	c.-150-79A>C		intron_variant		1		ENSP00000346478	P1
ADAMTSL2	ENST00000393060.1	c.-150-79A>C		intron_variant		1		ENSP00000376780	P1
ADAMTSL2	ENST00000393061.7	c.178-79A>C		intron_variant		1		ENSP00000376781

Frequencies

GnomAD3 genomes AF: 0.595 AC: 90532 AN: 152056 Hom.: 27459 Cov.: 34

Gnomad AFR AF: 0.615

Gnomad AMI AF: 0.661

Gnomad AMR AF: 0.456

Gnomad ASJ AF: 0.546

Gnomad EAS AF: 0.487

Gnomad SAS AF: 0.615

Gnomad FIN AF: 0.687

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.610

Gnomad OTH AF: 0.565

GnomAD4 exome AF: 0.601 AC: 796624 AN: 1324632 Hom.: 241286 AF XY: 0.601 AC XY: 386904 AN XY: 644038

Gnomad4 AFR exome AF: 0.607

Gnomad4 AMR exome AF: 0.361

Gnomad4 ASJ exome AF: 0.544

Gnomad4 EAS exome AF: 0.554

Gnomad4 SAS exome AF: 0.608

Gnomad4 FIN exome AF: 0.688

Gnomad4 NFE exome AF: 0.608

Gnomad4 OTH exome AF: 0.586

GnomAD4 genome AF: 0.595 AC: 90617 AN: 152174 Hom.: 27492 Cov.: 34 AF XY: 0.596 AC XY: 44326 AN XY: 74404

Gnomad4 AFR AF: 0.615

Gnomad4 AMR AF: 0.455

Gnomad4 ASJ AF: 0.546

Gnomad4 EAS AF: 0.486

Gnomad4 SAS AF: 0.615

Gnomad4 FIN AF: 0.687

Gnomad4 NFE AF: 0.610

Gnomad4 OTH AF: 0.567

Alfa AF: 0.609 Hom.: 3551

Bravo AF: 0.572

Asia WGS AF: 0.570 AC: 1984 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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	-	- -

Geleophysic dysplasia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.041
DANN	Benign	0.69

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: rs11507717; hg19: chr9-136401606; COSMIC: COSV63206446;