9-133537436-G-C

Position:

chr9-133537436-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_014694.4(ADAMTSL2):c.122G>C(p.Gly41Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000224 in 1,347,802 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

ADAMTSL2
NM_014694.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.36

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.064254284).

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000247 (295/1195582) while in subpopulation NFE AF= 0.000274 (267/973186). AF 95% confidence interval is 0.000247. There are 0 homozygotes in gnomad4_exome. There are 126 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTSL2	NM_014694.4 linkuse as main transcript	c.122G>C	p.Gly41Ala	missense_variant	3/19	ENST00000651351.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ADAMTSL2	ENST00000651351.2 linkuse as main transcript	c.122G>C	p.Gly41Ala	missense_variant	3/19		NM_014694.4	P1
ADAMTSL2	ENST00000393061.7 linkuse as main transcript	c.449G>C	p.Gly150Ala	missense_variant	3/19	1
ADAMTSL2	ENST00000354484.8 linkuse as main transcript	c.122G>C	p.Gly41Ala	missense_variant	3/19	1		P1
ADAMTSL2	ENST00000393060.1 linkuse as main transcript	c.122G>C	p.Gly41Ala	missense_variant	3/19	1		P1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000730

AC:

AN:

123226

Hom.:

AF XY:

0.0000751

AC XY:

AN XY:

66564

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000139

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000247

AC:

295

AN:

1195582

Hom.:

Cov.:

AF XY:

0.000219

AC XY:

126

AN XY:

576406

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000274

Gnomad4 OTH exome

AF:

0.000586

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0000723

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000693

Hom.:

Bravo

AF:

0.000128

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000590

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 06, 2023

The c.122G>C (p.G41A) alteration is located in exon 3 (coding exon 2) of the ADAMTSL2 gene. This alteration results from a G to C substitution at nucleotide position 122, causing the glycine (G) at amino acid position 41 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.64

CADD

Benign

7.4

DANN

Benign

0.78

DEOGEN2

Benign

0.011

T;T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.64

M_CAP

Benign

0.023

MetaRNN

Benign

0.064

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.97

L;.;L

MutationTaster

Benign

0.57

N;N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.57

N;N;N

REVEL

Benign

0.036

Sift

Benign

0.63

T;T;T

Sift4G

Benign

0.97

T;T;T

Polyphen

0.0010

B;.;B

Vest4

0.11

MVP

0.37

MPC

0.46

ClinPred

0.032

GERP RS

-1.8

Varity_R

0.050

gMVP

0.48

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