chr9-133536801-C-T

Variant summary

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

The NM_014694.4(ADAMTSL2):​c.89C>T​(p.Thr30Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,614,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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 (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

ADAMTSL2
NM_014694.4 missense, splice_region

Scores

1
17
Splicing: ADA: 0.0007944
2

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: -0.0330
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]

Genome browser will be placed here

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=0.10620868).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ADAMTSL2NM_014694.4 linkuse as main transcriptc.89C>T p.Thr30Met missense_variant, splice_region_variant 2/19 ENST00000651351.2 NP_055509.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ADAMTSL2ENST00000651351.2 linkuse as main transcriptc.89C>T p.Thr30Met missense_variant, splice_region_variant 2/19 NM_014694.4 ENSP00000498961 P1
ADAMTSL2ENST00000393061.7 linkuse as main transcriptc.416C>T p.Thr139Met missense_variant, splice_region_variant 2/191 ENSP00000376781
ADAMTSL2ENST00000354484.8 linkuse as main transcriptc.89C>T p.Thr30Met missense_variant, splice_region_variant 2/191 ENSP00000346478 P1
ADAMTSL2ENST00000393060.1 linkuse as main transcriptc.89C>T p.Thr30Met missense_variant, splice_region_variant 2/191 ENSP00000376780 P1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152208
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.0000724
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000359
AC:
9
AN:
250528
Hom.:
0
AF XY:
0.0000369
AC XY:
5
AN XY:
135548
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000145
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000185
AC:
27
AN:
1461830
Hom.:
0
Cov.:
33
AF XY:
0.0000193
AC XY:
14
AN XY:
727214
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.0000894
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000135
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152208
Hom.:
0
Cov.:
34
AF XY:
0.0000403
AC XY:
3
AN XY:
74360
show subpopulations
Gnomad4 AFR
AF:
0.0000724
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:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000264
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

ADAMTSL2-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesSep 07, 2024The ADAMTSL2 c.89C>T variant is predicted to result in the amino acid substitution p.Thr30Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.084
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.46
CADD
Benign
14
DANN
Benign
0.95
DEOGEN2
Benign
0.0091
T;T;T
Eigen
Benign
-0.47
Eigen_PC
Benign
-0.46
FATHMM_MKL
Benign
0.39
N
LIST_S2
Benign
0.64
.;T;T
M_CAP
Benign
0.055
D
MetaRNN
Benign
0.11
T;T;T
MetaSVM
Benign
-1.0
T
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.31
T
PROVEAN
Benign
0.0
N;N;N
REVEL
Benign
0.078
Sift
Uncertain
0.028
D;D;D
Sift4G
Benign
0.14
T;T;T
Polyphen
0.70
P;.;P
Vest4
0.15
MutPred
0.14
Loss of glycosylation at T30 (P = 0.0077);.;Loss of glycosylation at T30 (P = 0.0077);
MVP
0.66
MPC
0.51
ClinPred
0.43
T
GERP RS
1.1
Varity_R
0.030
gMVP
0.35

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00079
dbscSNV1_RF
Benign
0.028
SpliceAI score (max)
0.080
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.

Other links and lift over

dbSNP: rs762657949; hg19: chr9-136401923; API