chr9-133536484-A-C

Variant names:

• chr9-133536484-A-C
• rs11507717
• NM_014694.4:c.-150-79A>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 publications found

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]

ADAMTSL2 Gene-Disease associations (from GenCC):

• geleophysic dysplasia 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• Ehlers-Danlos syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014694.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTSL2	NM_014694.4	MANE Select	c.-150-79A>C		intron	N/A	NP_055509.2
	ADAMTSL2	NM_001145320.2		c.-150-79A>C		intron	N/A	NP_001138792.1	Q86TH1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTSL2	ENST00000651351.2	MANE Select	c.-150-79A>C		intron	N/A	ENSP00000498961.2	Q86TH1
	ADAMTSL2	ENST00000393061.7	TSL:1	c.178-79A>C		intron	N/A	ENSP00000376781.3	B1B0D4
	ADAMTSL2	ENST00000354484.8	TSL:1	c.-150-79A>C		intron	N/A	ENSP00000346478.4	Q86TH1

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

African (AFR) AF: 0.607 AC: 17960 AN: 29586

American (AMR) AF: 0.361 AC: 10194 AN: 28272

Ashkenazi Jewish (ASJ) AF: 0.544 AC: 11116 AN: 20428

East Asian (EAS) AF: 0.554 AC: 19387 AN: 34998

South Asian (SAS) AF: 0.608 AC: 41267 AN: 67836

European-Finnish (FIN) AF: 0.688 AC: 30664 AN: 44596

Middle Eastern (MID) AF: 0.481 AC: 2565 AN: 5328

European-Non Finnish (NFE) AF: 0.608 AC: 631347 AN: 1038804

Other (OTH) AF: 0.586 AC: 32124 AN: 54784

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

African (AFR) AF: 0.615 AC: 25534 AN: 41510

American (AMR) AF: 0.455 AC: 6962 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.546 AC: 1896 AN: 3472

East Asian (EAS) AF: 0.486 AC: 2514 AN: 5168

South Asian (SAS) AF: 0.615 AC: 2966 AN: 4822

European-Finnish (FIN) AF: 0.687 AC: 7297 AN: 10614

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.610 AC: 41489 AN: 67976

Other (OTH) AF: 0.567 AC: 1199 AN: 2114

Alfa AF: 0.609 Hom.: 3551

Bravo AF: 0.572

Asia WGS AF: 0.570 AC: 1984 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Geleophysic dysplasia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.041
DANN	Benign	0.69
PhyloP100		-2.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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