chr9-18504940-C-G

Variant summary

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

The NM_001040272.6(ADAMTSL1):ā€‹c.175C>Gā€‹(p.Arg59Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000249 in 1,609,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000026 ( 0 hom., cov: 33)
Exomes š‘“: 0.000025 ( 0 hom. )

Consequence

ADAMTSL1
NM_001040272.6 missense

Scores

4
8
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.33
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]

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=0.16055915).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ADAMTSL1NM_001040272.6 linkuse as main transcriptc.175C>G p.Arg59Gly missense_variant 2/29 ENST00000380548.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ADAMTSL1ENST00000380548.9 linkuse as main transcriptc.175C>G p.Arg59Gly missense_variant 2/295 NM_001040272.6 P1Q8N6G6-3

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152210
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000770
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000122
AC:
30
AN:
245986
Hom.:
0
AF XY:
0.0000750
AC XY:
10
AN XY:
133394
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00166
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:
0.0000247
AC:
36
AN:
1457138
Hom.:
0
Cov.:
33
AF XY:
0.0000234
AC XY:
17
AN XY:
725090
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000858
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000332
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152210
Hom.:
0
Cov.:
33
AF XY:
0.0000403
AC XY:
3
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000770
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000453
ExAC
AF:
0.000107
AC:
13

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 20, 2023The c.175C>G (p.R59G) alteration is located in exon 2 (coding exon 2) of the ADAMTSL1 gene. This alteration results from a C to G substitution at nucleotide position 175, causing the arginine (R) at amino acid position 59 to be replaced by a glycine (G). 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
Pathogenic
0.94
BayesDel_addAF
Benign
-0.036
T
BayesDel_noAF
Pathogenic
0.15
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.22
.;T;.;.;.;.;.
Eigen
Uncertain
0.39
Eigen_PC
Uncertain
0.36
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.88
D;D;D;D;D;D;D
M_CAP
Benign
0.076
D
MetaRNN
Benign
0.16
T;T;T;T;T;T;T
MetaSVM
Benign
-0.63
T
MutationAssessor
Benign
1.4
.;L;L;.;.;L;L
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Uncertain
0.77
T
PROVEAN
Uncertain
-3.7
.;D;D;D;D;D;D
REVEL
Uncertain
0.43
Sift
Pathogenic
0.0
.;D;D;D;D;D;D
Sift4G
Uncertain
0.0050
.;D;T;T;T;T;D
Polyphen
1.0, 0.99
.;D;.;.;.;D;.
Vest4
0.84, 0.89, 0.87, 0.88, 0.86, 0.88
MutPred
0.57
.;Loss of MoRF binding (P = 0.0185);Loss of MoRF binding (P = 0.0185);Loss of MoRF binding (P = 0.0185);Loss of MoRF binding (P = 0.0185);Loss of MoRF binding (P = 0.0185);Loss of MoRF binding (P = 0.0185);
MVP
0.57
MPC
0.45
ClinPred
0.31
T
GERP RS
3.3
Varity_R
0.67
gMVP
0.63

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs769527362; hg19: chr9-18504938; COSMIC: COSV105108084; API