rs145897018

Variant names:

• chr9-133536770-G-A
• rs145897018
• NM_014694.4:c.58G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_014694.4(ADAMTSL2):​c.58G>A​(p.Val20Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,614,220 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0013 (4 hom.)
• Consequence: ADAMTSL2 NM_014694.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 1.86
• Publications: 7 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005418688).
• BP6: Variant 9-133536770-G-A is Benign according to our data. Variant chr9-133536770-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 365571.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00123 (187/152356) while in subpopulation NFE AF = 0.00178 (121/68038). AF 95% confidence interval is 0.00152. There are 0 homozygotes in GnomAd4. There are 76 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR,AD gene

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.58G>A	p.Val20Ile	missense	Exon 2 of 19	NP_055509.2
	ADAMTSL2	NM_001145320.2		c.58G>A	p.Val20Ile	missense	Exon 2 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.58G>A	p.Val20Ile	missense	Exon 2 of 19	ENSP00000498961.2	Q86TH1
	ADAMTSL2	ENST00000393061.7	TSL:1	c.385G>A	p.Val129Ile	missense	Exon 2 of 19	ENSP00000376781.3	B1B0D4
	ADAMTSL2	ENST00000354484.8	TSL:1	c.58G>A	p.Val20Ile	missense	Exon 2 of 19	ENSP00000346478.4	Q86TH1

Frequencies

GnomAD3 genomes AF: 0.00123 AC: 187 AN: 152238 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00178

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00154 AC: 388 AN: 251258 AF XY: 0.00146

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00894

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00186

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00134 AC: 1965 AN: 1461864 Hom.: 4 Cov.: 33 AF XY: 0.00131 AC XY: 954 AN XY: 727228

African (AFR) AF: 0.000299 AC: 10 AN: 33480

American (AMR) AF: 0.00152 AC: 68 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00880 AC: 230 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000325 AC: 28 AN: 86258

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53402

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5766

European-Non Finnish (NFE) AF: 0.00136 AC: 1515 AN: 1112006

Other (OTH) AF: 0.00157 AC: 95 AN: 60394

GnomAD4 genome AF: 0.00123 AC: 187 AN: 152356 Hom.: 0 Cov.: 34 AF XY: 0.00102 AC XY: 76 AN XY: 74510

African (AFR) AF: 0.000289 AC: 12 AN: 41590

American (AMR) AF: 0.000457 AC: 7 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00178 AC: 121 AN: 68038

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00185 Hom.: 1

Bravo AF: 0.00122

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00141 AC: 171

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00360

EpiControl AF: 0.00267

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	Geleophysic dysplasia 1 (3)
-	1	1	not provided (2)
-	-	1	ADAMTSL2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	12
DANN	Benign	0.072
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.9
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.047
Sift	Benign	0.38	T
Sift4G	Benign	0.72	T
Polyphen		0.0	B
Vest4		0.30
MVP		0.46
MPC		0.35
ClinPred		0.0011	T
GERP RS		2.4
Varity_R		0.024
gMVP		0.15
Mutation Taster		=100/0	polymorphism

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: rs145897018; hg19: chr9-136401892;