Genetic Variant NM_007037.6:c.2170C>T (chr11-130406058-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_007037.6(ADAMTS8):c.2170C>T(p.Pro724Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. P724A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ADAMTS8
NM_007037.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.392

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]

ADAMTS8 links:

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=0.111320764).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS8	NM_007037.6 link	c.2170C>T	p.Pro724Ser	missense_variant	Exon 9 of 9	ENST00000257359.7	NP_008968.4
ADAMTS8	XM_017017145.2 link	c.2122C>T	p.Pro708Ser	missense_variant	Exon 9 of 9		XP_016872634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS8	ENST00000257359.7 link	c.2170C>T	p.Pro724Ser	missense_variant	Exon 9 of 9	1	NM_007037.6	ENSP00000257359.6		Q9UP79
ADAMTS8	ENST00000531752.1 link	n.1117C>T		non_coding_transcript_exon_variant	Exon 4 of 4	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000803

AC:

AN:

249040

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135278

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

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:

6.84e-7

AC:

AN:

1461650

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727140

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0038

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.37

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.75

M_CAP

Benign

0.015

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.39

PrimateAI

Benign

0.37

PROVEAN

Benign

0.080

REVEL

Benign

0.044

Sift

Benign

0.19

Sift4G

Benign

0.25

Polyphen

0.0090

Vest4

0.065

MutPred

0.45

Gain of glycosylation at P724 (P = 0.0468);

MVP

0.47

MPC

0.26

ClinPred

0.10

GERP RS

3.3

Varity_R

0.066

gMVP

0.45

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over