rs770666720

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_007037.6(ADAMTS8):​c.2564G>T​(p.Arg855Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R855Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

ADAMTS8
NM_007037.6 missense

Scores

12
4
3

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.79
Variant links:
Genes affected
ADAMTS8 (HGNC:224): (ADAM metallopeptidase with thrombospondin type 1 motif 8) This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) 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 encoded preproprotein is proteolytically processed to generate the mature enzyme. This enzyme contains two C-terminal TS motifs, and disrupts angiogenesis in vivo. A number of disorders have been mapped in the vicinity of this gene, most notably lung neoplasms. Reduced expression of this gene has been observed in multiple human cancers and this gene has been proposed as a potential tumor suppressor. [provided by RefSeq, Feb 2016]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.91

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ADAMTS8NM_007037.6 linkc.2564G>T p.Arg855Leu missense_variant Exon 9 of 9 ENST00000257359.7 NP_008968.4
ADAMTS8XM_017017145.2 linkc.2516G>T p.Arg839Leu missense_variant Exon 9 of 9 XP_016872634.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ADAMTS8ENST00000257359.7 linkc.2564G>T p.Arg855Leu missense_variant Exon 9 of 9 1 NM_007037.6 ENSP00000257359.6 Q9UP79
ADAMTS8ENST00000531752.1 linkn.1511G>T non_coding_transcript_exon_variant Exon 4 of 4 2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000547
AC:
8
AN:
1461708
Hom.:
0
Cov.:
31
AF XY:
0.00000688
AC XY:
5
AN XY:
727134
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000630
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.81
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.37
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.096
T
Eigen
Pathogenic
0.81
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Uncertain
0.14
D
MetaRNN
Pathogenic
0.91
D
MetaSVM
Pathogenic
0.90
D
MutationAssessor
Pathogenic
4.0
H
PrimateAI
Benign
0.39
T
PROVEAN
Pathogenic
-6.0
D
REVEL
Pathogenic
0.77
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0020
D
Polyphen
0.99
D
Vest4
0.94
MutPred
0.61
Loss of disorder (P = 0.0417);
MVP
0.95
MPC
0.90
ClinPred
1.0
D
GERP RS
4.4
Varity_R
0.82
gMVP
0.86

Splicing

Name
Calibrated prediction
Score
Prediction
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-130275559; API