Genetic Variant ADAMTS6:p.Leu909Phe (chr5-65188199-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_197941.4(ADAMTS6):c.2727G>C(p.Leu909Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000566 in 1,613,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00060 ( 0 hom. )

Consequence

ADAMTS6
NM_197941.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.268

Publications

1 publications found

Variant links:

Genes affected

ADAMTS6 (HGNC:222): (ADAM metallopeptidase with thrombospondin type 1 motif 6) 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. Expression of this gene may be regulated by the cytokine TNF-alpha. [provided by RefSeq, Mar 2016]

ADAMTS6 Gene-Disease associations (from GenCC):

Tourette syndrome
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ADAMTS6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07230973).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_197941.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS6	NM_197941.4	MANE Select	c.2727G>C	p.Leu909Phe	missense	Exon 22 of 25	NP_922932.2	Q9UKP5-1
	ADAMTS6	NR_135689.2		n.3735G>C		non_coding_transcript_exon	Exon 23 of 26

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADAMTS6	ENST00000381055.8	TSL:1 MANE Select	c.2727G>C	p.Leu909Phe	missense	Exon 22 of 25	ENSP00000370443.3	Q9UKP5-1
ADAMTS6	ENST00000314351.9	TSL:2	n.387G>C		non_coding_transcript_exon	Exon 3 of 6
ADAMTS6	ENST00000381052.8	TSL:2	n.*1999G>C		non_coding_transcript_exon	Exon 23 of 26	ENSP00000424377.1	Q9UKP5-4

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000239

AC:

AN:

250740

AF XY:

0.000244

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000450

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.000598

AC:

874

AN:

1461658

Hom.:

Cov.:

AF XY:

0.000551

AC XY:

401

AN XY:

727140

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53284

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.000761

AC:

846

AN:

1111970

Other (OTH)

AF:

0.000364

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

102

153

204

255

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

132

176

220

<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

AF:

0.000256

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41452

American (AMR)

AF:

0.0000654

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000382

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000427

Hom.:

Bravo

AF:

0.000314

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000239

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.030

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.092

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.010

MetaRNN

Benign

0.072

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.83

PhyloP100

-0.27

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.44

REVEL

Benign

0.11

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0040

Polyphen

0.056

Vest4

0.33

MutPred

0.36

Loss of ubiquitination at K913 (P = 0.1016)

MVP

0.18

MPC

0.77

ClinPred

0.089

GERP RS

4.5

Varity_R

0.23

gMVP

0.21

Mutation Taster

=88/12

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over