chr9-18574073-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP3BP4_Moderate

The NM_001040272.6(ADAMTSL1):​c.281C>T​(p.Ser94Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000152 in 1,614,068 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00079 ( 1 hom., cov: 32)
Exomes 𝑓: 0.000086 ( 0 hom. )

Consequence

ADAMTSL1
NM_001040272.6 missense

Scores

6
7
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.74
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 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Multiple lines of computational evidence support a deleterious effect 7: Cadd, Dann, Eigen, FATHMM_MKL, MutationAssessor, phyloP100way_vertebrate, PROVEAN [when BayesDel_addAF, max_spliceai, M_CAP, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.10956225).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ADAMTSL1NM_001040272.6 linkuse as main transcriptc.281C>T p.Ser94Leu missense_variant 4/29 ENST00000380548.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ADAMTSL1ENST00000380548.9 linkuse as main transcriptc.281C>T p.Ser94Leu missense_variant 4/295 NM_001040272.6 P1Q8N6G6-3

Frequencies

GnomAD3 genomes
AF:
0.000789
AC:
120
AN:
152128
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00746
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:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000330
AC:
83
AN:
251194
Hom.:
0
AF XY:
0.000302
AC XY:
41
AN XY:
135756
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.00220
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:
0.0000176
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.0000855
AC:
125
AN:
1461822
Hom.:
0
Cov.:
31
AF XY:
0.0000770
AC XY:
56
AN XY:
727220
show subpopulations
Gnomad4 AFR exome
AF:
0.000269
Gnomad4 AMR exome
AF:
0.00212
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000108
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
AF:
0.000788
AC:
120
AN:
152246
Hom.:
1
Cov.:
32
AF XY:
0.00118
AC XY:
88
AN XY:
74442
show subpopulations
Gnomad4 AFR
AF:
0.000120
Gnomad4 AMR
AF:
0.00745
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.0000510
Hom.:
0
Bravo
AF:
0.000778
ExAC
AF:
0.0000988
AC:
12

ClinVar

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

Submissions by phenotype

Orofacial cleft 1 Uncertain:1
Uncertain significance, criteria provided, single submitterresearchGrupo de Genetica Humana, Facultad de Medicina - Universidad de La SabanaNov 22, 2022This variant affects ADAMTSL1, a gene whose malfunction has been associated with many craniofacial defects, such as brachycephaly, microcephaly, prominent cupid’s bow, short philtrum, wide and flat nasal bridge and prominent mandible. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.49
BayesDel_addAF
Benign
-0.061
T
BayesDel_noAF
Uncertain
0.13
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.28
T;.;.;.;.;.
Eigen
Pathogenic
0.94
Eigen_PC
Pathogenic
0.89
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D;D;D;D;D
M_CAP
Benign
0.055
D
MetaRNN
Benign
0.11
T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Pathogenic
3.5
M;M;.;.;M;M
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Uncertain
0.79
T
PROVEAN
Uncertain
-4.0
D;D;D;D;D;D
REVEL
Uncertain
0.58
Sift
Pathogenic
0.0
D;D;D;D;D;D
Sift4G
Uncertain
0.0020
D;D;D;D;D;T
Polyphen
1.0
D;.;.;.;D;.
Vest4
0.85
MVP
0.60
MPC
0.38
ClinPred
0.28
T
GERP RS
5.5
Varity_R
0.52
gMVP
0.53

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: rs190050504; hg19: chr9-18574071; API