NM_014694.4:c.199G>A

Variant names:

• chr9-133537513-G-A
• NM_014694.4:c.199G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014694.4(ADAMTSL2):​c.199G>A​(p.Val67Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ADAMTSL2 NM_014694.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.67
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838

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.199G>A	p.Val67Met	missense	Exon 3 of 19	NP_055509.2
	ADAMTSL2	NM_001145320.2		c.199G>A	p.Val67Met	missense	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.199G>A	p.Val67Met	missense	Exon 3 of 19	ENSP00000498961.2	Q86TH1
	ADAMTSL2	ENST00000393061.7	TSL:1	c.526G>A	p.Val176Met	missense	Exon 3 of 19	ENSP00000376781.3	B1B0D4
	ADAMTSL2	ENST00000354484.8	TSL:1	c.199G>A	p.Val67Met	missense	Exon 3 of 19	ENSP00000346478.4	Q86TH1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1200042 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 578882

African (AFR) AF: 0.00 AC: 0 AN: 25248

American (AMR) AF: 0.00 AC: 0 AN: 19664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16080

East Asian (EAS) AF: 0.00 AC: 0 AN: 30918

South Asian (SAS) AF: 0.00 AC: 0 AN: 37356

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 975592

Other (OTH) AF: 0.00 AC: 0 AN: 48072

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

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
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.19	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.7
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.59		Loss of catalytic residue at V67 (P = 0.0064)
MVP		0.66
MPC		1.3
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.84
gMVP		0.67
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

hg19: chr9-136402635;