rs371831041

Variant names:

• chr9-133537512-G-A
• rs371831041
• NM_014694.4:c.198G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_014694.4(ADAMTSL2):​c.198G>A​(p.Gly66Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000621 in 1,352,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: ADAMTSL2 NM_014694.4 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.763
• 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Ehlers-Danlos syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 9-133537512-G-A is Benign according to our data. Variant chr9-133537512-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3352484.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.763 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000322 (49/152352) while in subpopulation AFR AF = 0.00106 (44/41582). AF 95% confidence interval is 0.000809. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.198G>A	p.Gly66Gly	synonymous	Exon 3 of 19	NP_055509.2
	ADAMTSL2	NM_001145320.2		c.198G>A	p.Gly66Gly	synonymous	Exon 3 of 19	NP_001138792.1	Q86TH1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTSL2	ENST00000651351.2	MANE Select	c.198G>A	p.Gly66Gly	synonymous	Exon 3 of 19	ENSP00000498961.2	Q86TH1
	ADAMTSL2	ENST00000393061.7	TSL:1	c.525G>A	p.Gly175Gly	synonymous	Exon 3 of 19	ENSP00000376781.3	B1B0D4
	ADAMTSL2	ENST00000354484.8	TSL:1	c.198G>A	p.Gly66Gly	synonymous	Exon 3 of 19	ENSP00000346478.4	Q86TH1

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000975 AC: 12 AN: 123080 AF XY: 0.0000904

Gnomad AFR exome AF: 0.00110

Gnomad AMR exome AF: 0.0000872

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000292 AC: 35 AN: 1200214 Hom.: 0 Cov.: 30 AF XY: 0.0000276 AC XY: 16 AN XY: 578986

African (AFR) AF: 0.00131 AC: 33 AN: 25260

American (AMR) AF: 0.0000510 AC: 1 AN: 19620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16096

East Asian (EAS) AF: 0.00 AC: 0 AN: 30914

South Asian (SAS) AF: 0.00 AC: 0 AN: 37500

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42362

Middle Eastern (MID) AF: 0.000210 AC: 1 AN: 4752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 975624

Other (OTH) AF: 0.00 AC: 0 AN: 48086

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152352 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74500

African (AFR) AF: 0.00106 AC: 44 AN: 41582

American (AMR) AF: 0.000261 AC: 4 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000330 Hom.: 0

Bravo AF: 0.000355

ClinVar

ClinVar submissions as Germline

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	-0.55
CADD	Benign	8.5
DANN	Benign	0.77
PhyloP100		-0.76
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs371831041; hg19: chr9-136402634;