chr9-18574073-C-T
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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
NM_001040272.6 missense
Scores
6
7
6
Clinical Significance
Conservation
PhyloP100: 7.74
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]
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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 |
---|---|---|---|---|---|---|---|
ADAMTSL1 | NM_001040272.6 | c.281C>T | p.Ser94Leu | missense_variant | 4/29 | ENST00000380548.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADAMTSL1 | ENST00000380548.9 | c.281C>T | p.Ser94Leu | missense_variant | 4/29 | 5 | NM_001040272.6 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000789 AC: 120AN: 152128Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000330 AC: 83AN: 251194Hom.: 0 AF XY: 0.000302 AC XY: 41AN XY: 135756
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GnomAD4 exome AF: 0.0000855 AC: 125AN: 1461822Hom.: 0 Cov.: 31 AF XY: 0.0000770 AC XY: 56AN XY: 727220
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GnomAD4 genome AF: 0.000788 AC: 120AN: 152246Hom.: 1 Cov.: 32 AF XY: 0.00118 AC XY: 88AN XY: 74442
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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 submitter | research | Grupo de Genetica Humana, Facultad de Medicina - Universidad de La Sabana | Nov 22, 2022 | This 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;.;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;M;.;.;M;M
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D;D
REVEL
Uncertain
Sift
Pathogenic
D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;T
Polyphen
D;.;.;.;D;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at