NM_014694.4:c.340G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_014694.4(ADAMTSL2):c.340G>A(p.Glu114Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,545,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

ADAMTSL2
NM_014694.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1O:1

Conservation

PhyloP100: 7.33

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.907

PP5

Variant 9-133539801-G-A is Pathogenic according to our data. Variant chr9-133539801-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 695.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=2, not_provided=1}. Variant chr9-133539801-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTSL2	NM_014694.4 link	c.340G>A	p.Glu114Lys	missense_variant	Exon 5 of 19	ENST00000651351.2	NP_055509.2	Q86TH1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADAMTSL2	ENST00000651351.2 link	c.340G>A	p.Glu114Lys	missense_variant	Exon 5 of 19		NM_014694.4	ENSP00000498961.2	Q86TH1
ADAMTSL2	ENST00000393061.7 link	c.667G>A	p.Glu223Lys	missense_variant	Exon 5 of 19	1		ENSP00000376781.3	B1B0D4
ADAMTSL2	ENST00000354484.8 link	c.340G>A	p.Glu114Lys	missense_variant	Exon 5 of 19	1		ENSP00000346478.4	Q86TH1
ADAMTSL2	ENST00000393060.1 link	c.340G>A	p.Glu114Lys	missense_variant	Exon 5 of 19	1		ENSP00000376780.1	Q86TH1

Frequencies

GnomAD3 genomes

AF:

0.0000204

AC:

AN:

147210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000501

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:

0.0000150

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000641

AC:

AN:

155966

Hom.:

AF XY:

0.0000122

AC XY:

AN XY:

82136

show subpopulations

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 SAS exome

AF:

0.0000439

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000100

AC:

AN:

1398662

Hom.:

Cov.:

AF XY:

0.0000101

AC XY:

AN XY:

689854

show subpopulations

Gnomad4 AFR exome

AF:

0.0000633

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000397

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000834

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000204

AC:

AN:

147210

Hom.:

Cov.:

AF XY:

0.0000140

AC XY:

AN XY:

71662

show subpopulations

Gnomad4 AFR

AF:

0.0000501

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000150

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Geleophysic dysplasia 1

Pathogenic:3Other:1

Jun 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 17, 2017

Laboratory of Metabolic Disorders, Peking University First Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1Uncertain:1

Sep 10, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21415077, 33082559, 30195254, 18677313, 28917829) -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Geleophysic dysplasia

Pathogenic:1

Jun 21, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ADAMTSL2 c.340G>A (p.Glu114Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-06 in 155966 control chromosomes. c.340G>A has been reported in the literature in multiple individuals affected with Geleophysic Dysplasia as a homozygous, compound heterozygous, or unspecified genotype (e.g. Allali_2011, LeGoff_2008, Li_2017, Marzin_2021), including a de novo occurrence in a compound heterozygous individual (Li_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21415077, 18677313, 28917829, 33082559). ClinVar contains an entry for this variant (Variation ID: 695). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.072

T;T;T

Eigen

Uncertain

0.67

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

.;D;D

M_CAP

Uncertain

0.085

MetaRNN

Pathogenic

0.91

D;D;D

MetaSVM

Benign

-0.53

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-2.2

N;N;N

REVEL

Uncertain

0.50

Sift

Uncertain

0.0070

D;D;D

Sift4G

Uncertain

0.013

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.92

MutPred

0.78

Gain of ubiquitination at E114 (P = 0.0177);.;Gain of ubiquitination at E114 (P = 0.0177);

MVP

0.80

MPC

1.1

ClinPred

0.99

GERP RS

5.5

Varity_R

0.38

gMVP

0.86

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over