chr3-64533167-G-A

Position:

chr3-64533167-G-A

Variant summary

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

The NM_182920.2(ADAMTS9):c.5717C>T(p.Pro1906Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,611,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

ADAMTS9
NM_182920.2 missense, splice_region

Scores

Splicing: ADA: 0.0008122

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.02

Variant links:

Genes affected

ADAMTS9 (HGNC:13202): (ADAM metallopeptidase with thrombospondin type 1 motif 9) 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. Members of the ADAMTS family have been implicated in the cleavage of proteoglycans, the control of organ shape during development, and the inhibition of angiogenesis. This gene is localized to chromosome 3p14.3-p14.2, an area known to be lost in hereditary renal tumors. Alternative splicing results in multiple transcript variants encoding different isoforms that may undergo similar proteolytic processing. [provided by RefSeq, Jan 2016]

ADAMTS9 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=0.23846325).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ADAMTS9	NM_182920.2 linkuse as main transcript	c.5717C>T	p.Pro1906Leu	missense_variant, splice_region_variant	38/40	ENST00000498707.5	NP_891550.1
ADAMTS9	NM_001318781.2 linkuse as main transcript	c.5633C>T	p.Pro1878Leu	missense_variant, splice_region_variant	37/39		NP_001305710.1
ADAMTS9	XR_007095711.1 linkuse as main transcript	n.5976C>T		splice_region_variant, non_coding_transcript_exon_variant	37/40
ADAMTS9	XR_245151.1 linkuse as main transcript	n.6060C>T		splice_region_variant, non_coding_transcript_exon_variant	38/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS9	ENST00000498707.5 linkuse as main transcript	c.5717C>T	p.Pro1906Leu	missense_variant, splice_region_variant	38/40	1	NM_182920.2	ENSP00000418735	P1	Q9P2N4-3
ADAMTS9	ENST00000295903.8 linkuse as main transcript	c.5633C>T	p.Pro1878Leu	missense_variant, splice_region_variant	37/39	1		ENSP00000295903		Q9P2N4-4
ADAMTS9	ENST00000481060.2 linkuse as main transcript	c.2885C>T	p.Pro962Leu	missense_variant, splice_region_variant	19/21	2		ENSP00000417521
ADAMTS9	ENST00000467257.5 linkuse as main transcript	c.119C>T	p.Pro40Leu	missense_variant, splice_region_variant, NMD_transcript_variant	2/5	5		ENSP00000478086

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000598

AC:

AN:

250836

Hom.:

AF XY:

0.0000812

AC XY:

AN XY:

135536

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000123

AC:

179

AN:

1459736

Hom.:

Cov.:

AF XY:

0.000132

AC XY:

AN XY:

726250

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000153

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000693

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.5717C>T (p.P1906L) alteration is located in exon 38 (coding exon 38) of the ADAMTS9 gene. This alteration results from a C to T substitution at nucleotide position 5717, causing the proline (P) at amino acid position 1906 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.12

T;.

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.74

T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.24

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.1

L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-2.6

D;D

REVEL

Benign

0.062

Sift

Benign

0.37

T;T

Sift4G

Benign

0.18

T;T

Polyphen

0.0

B;.

Vest4

0.30

MutPred

0.55

Loss of disorder (P = 0.0343);.;

MVP

0.50

MPC

0.20

ClinPred

0.079

GERP RS

3.3

Varity_R

0.072

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00081

dbscSNV1_RF

Benign

0.020

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over