Genetic Variant ADAMTSL1:p.Val79Ala (chr9-18533291-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001040272.6(ADAMTSL1):c.236T>C(p.Val79Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ADAMTSL1
NM_001040272.6 missense, splice_region

Scores

Splicing: ADA: 0.009919

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.34

Variant links:

Genes affected

ADAMTSL1 (HGNC:14632): (ADAMTS like 1) This gene encodes a secreted protein and member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motif) family. This protein lacks the metalloproteinase and disintegrin-like domains, which are typical of the ADAMTS family, but contains other ADAMTS domains, including the thrombospondin type 1 motif. This protein may have important functions in the extracellular matrix. Alternative splicing results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, Jul 2008]

ADAMTSL1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18760309).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTSL1	NM_001040272.6 link	c.236T>C	p.Val79Ala	missense_variant, splice_region_variant	Exon 3 of 29	ENST00000380548.9	NP_001035362.3	Q8N6G6-3Q6MZQ3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTSL1	ENST00000380548.9 link	c.236T>C	p.Val79Ala	missense_variant, splice_region_variant	Exon 3 of 29	5	NM_001040272.6	ENSP00000369921.4		Q8N6G6-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000403

AC:

AN:

247930

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134078

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000297

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457028

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724790

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000226

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.236T>C (p.V79A) alteration is located in exon 3 (coding exon 3) of the ADAMTSL1 gene. This alteration results from a T to C substitution at nucleotide position 236, causing the valine (V) at amino acid position 79 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

0.17

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.014

.;T;.;.;.;.;.

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.014

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.89

D;T;T;T;T;T;T

M_CAP

Benign

0.025

MetaRNN

Benign

0.19

T;T;T;T;T;T;T

MetaSVM

Benign

-0.73

MutationAssessor

Benign

-0.28

.;N;N;.;.;N;N

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

0.0

.;N;N;N;N;N;N

REVEL

Benign

0.23

Sift

Benign

0.46

.;T;T;T;T;T;T

Sift4G

Benign

0.95

.;T;T;T;T;T;T

Polyphen

0.13, 0.021

.;B;.;.;.;B;.

Vest4

0.56, 0.56, 0.55, 0.53, 0.57, 0.56

MutPred

0.44

.;Gain of disorder (P = 0.027);Gain of disorder (P = 0.027);Gain of disorder (P = 0.027);Gain of disorder (P = 0.027);Gain of disorder (P = 0.027);Gain of disorder (P = 0.027);

MVP

0.32

MPC

0.12

ClinPred

0.17

GERP RS

5.2

Varity_R

0.052

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0099

dbscSNV1_RF

Benign

0.12

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