rs200940324

Variant names:

• chr9-133537400-C-T
• rs200940324
• NM_014694.4:c.91-5C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_014694.4(ADAMTSL2):​c.91-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000358 in 1,339,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: ADAMTSL2 NM_014694.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001261
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.337
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 9-133537400-C-T is Benign according to our data. Variant chr9-133537400-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3054919.Status of the report is no_assertion_criteria_provided, 0 stars.

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.91-5C>T		splice_region intron	N/A	NP_055509.2
	ADAMTSL2	NM_001145320.2		c.91-5C>T		splice_region 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.91-5C>T		splice_region intron	N/A	ENSP00000498961.2	Q86TH1
	ADAMTSL2	ENST00000393061.7	TSL:1	c.418-5C>T		splice_region intron	N/A	ENSP00000376781.3	B1B0D4
	ADAMTSL2	ENST00000354484.8	TSL:1	c.91-5C>T		splice_region intron	N/A	ENSP00000346478.4	Q86TH1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000808 AC: 1 AN: 123836 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000154

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000396 AC: 47 AN: 1187510 Hom.: 0 Cov.: 30 AF XY: 0.0000367 AC XY: 21 AN XY: 571634

African (AFR) AF: 0.00 AC: 0 AN: 25210

American (AMR) AF: 0.00 AC: 0 AN: 19562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15832

East Asian (EAS) AF: 0.00 AC: 0 AN: 30822

South Asian (SAS) AF: 0.00 AC: 0 AN: 33742

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4716

European-Non Finnish (NFE) AF: 0.0000465 AC: 45 AN: 968698

Other (OTH) AF: 0.0000421 AC: 2 AN: 47538

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74354

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000996 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	ADAMTSL2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.7
DANN	Benign	0.54
PhyloP100		-0.34

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000013
dbscSNV1_RF	Benign	0.0
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: rs200940324; hg19: chr9-136402522;