Genetic Variant ADAMTS8:p.Tyr703* (chr11-130406119-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_007037.6(ADAMTS8):c.2109C>A(p.Tyr703*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.00030 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ADAMTS8
NM_007037.6 stop_gained

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 2.57

Publications

6 publications found

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:

ZBTB44-DT (HGNC:54265): (ZBTB44 divergent transcript)

ZBTB44-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS8	NM_007037.6 link	c.2109C>A	p.Tyr703*	stop_gained	Exon 9 of 9	ENST00000257359.7	NP_008968.4
ADAMTS8	XM_017017145.2 link	c.2061C>A	p.Tyr687*	stop_gained	Exon 9 of 9		XP_016872634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADAMTS8	ENST00000257359.7 link	c.2109C>A	p.Tyr703*	stop_gained	Exon 9 of 9	1	NM_007037.6	ENSP00000257359.6	Q9UP79
ADAMTS8	ENST00000531752.1 link	n.1056C>A		non_coding_transcript_exon_variant	Exon 4 of 4	2
ZBTB44-DT	ENST00000777858.1 link	n.320+12320G>T		intron_variant	Intron 3 of 4
ZBTB44-DT	ENST00000777859.1 link	n.870+12320G>T		intron_variant	Intron 8 of 9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00280

AC:

667

AN:

238236

AF XY:

0.00174

show subpopulations

Gnomad AFR exome

AF:

0.00770

Gnomad AMR exome

AF:

0.000262

Gnomad ASJ exome

AF:

0.00132

Gnomad EAS exome

AF:

0.000448

Gnomad FIN exome

AF:

0.00103

Gnomad NFE exome

AF:

0.00449

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000304

AC:

442

AN:

1453214

Hom.:

Cov.:

AF XY:

0.000321

AC XY:

232

AN XY:

722844

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33450

American (AMR)

AF:

0.00

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39634

South Asian (SAS)

AF:

0.00

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.00624

AC:

291

AN:

46652

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000107

AC:

119

AN:

1110590

Other (OTH)

AF:

0.000533

AC:

AN:

60088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000131

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00714

AC:

834

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Oromandibular-limb hypogenesis spectrum

Uncertain:1

Aug 12, 2016

CHU Sainte-Justine Research Center, University of Montreal

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.92

PhyloP100

2.6

Vest4

0.30

GERP RS

3.4

Mutation Taster

=1/199

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.38

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.38

Position offset: -23

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over