rs28569945

Variant names:

• chr9-133536945-G-T
• rs28569945
• NM_014694.4:c.90+143G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_014694.4(ADAMTSL2):​c.90+143G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 1,390,364 control chromosomes in the GnomAD database, including 35,467 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.24 (4761 hom., cov: 33)
  • Exomes 𝑓: 0.21 (30706 hom.)
• Consequence: ADAMTSL2 NM_014694.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.53
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 9-133536945-G-T is Benign according to our data. Variant chr9-133536945-G-T is described in ClinVar as Benign. ClinVar VariationId is 1225896.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.329 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.90+143G>T		intron	N/A	NP_055509.2
	ADAMTSL2	NM_001145320.2		c.90+143G>T		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.90+143G>T		intron	N/A	ENSP00000498961.2	Q86TH1
	ADAMTSL2	ENST00000393061.7	TSL:1	c.417+143G>T		intron	N/A	ENSP00000376781.3	B1B0D4
	ADAMTSL2	ENST00000354484.8	TSL:1	c.90+143G>T		intron	N/A	ENSP00000346478.4	Q86TH1

Frequencies

GnomAD3 genomes AF: 0.237 AC: 36052 AN: 152084 Hom.: 4752 Cov.: 33

Gnomad AFR AF: 0.333

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.134

Gnomad EAS AF: 0.0264

Gnomad SAS AF: 0.0713

Gnomad FIN AF: 0.224

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.223

Gnomad OTH AF: 0.231

GnomAD4 exome AF: 0.214 AC: 264477 AN: 1238162 Hom.: 30706 AF XY: 0.209 AC XY: 127106 AN XY: 607102

African (AFR) AF: 0.329 AC: 9203 AN: 28002

American (AMR) AF: 0.148 AC: 4291 AN: 28988

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 2635 AN: 20112

East Asian (EAS) AF: 0.0312 AC: 1092 AN: 34974

South Asian (SAS) AF: 0.0766 AC: 5080 AN: 66358

European-Finnish (FIN) AF: 0.228 AC: 9553 AN: 41904

Middle Eastern (MID) AF: 0.163 AC: 581 AN: 3574

European-Non Finnish (NFE) AF: 0.230 AC: 221294 AN: 962340

Other (OTH) AF: 0.207 AC: 10748 AN: 51910

GnomAD4 genome AF: 0.237 AC: 36091 AN: 152202 Hom.: 4761 Cov.: 33 AF XY: 0.232 AC XY: 17260 AN XY: 74412

African (AFR) AF: 0.333 AC: 13830 AN: 41506

American (AMR) AF: 0.200 AC: 3053 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 466 AN: 3472

East Asian (EAS) AF: 0.0264 AC: 137 AN: 5182

South Asian (SAS) AF: 0.0709 AC: 342 AN: 4822

European-Finnish (FIN) AF: 0.224 AC: 2375 AN: 10606

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.223 AC: 15185 AN: 67998

Other (OTH) AF: 0.228 AC: 481 AN: 2112

Alfa AF: 0.229 Hom.: 6031

Bravo AF: 0.242

Asia WGS AF: 0.0800 AC: 280 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.35
DANN	Benign	0.62
PhyloP100		-1.5
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: rs28569945; hg19: chr9-136402067; COSMIC: COSV63203581;