chr3-64533252-G-C

Position:

chr3-64533252-G-C

Variant summary

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

The NM_182920.2(ADAMTS9):c.5632C>G(p.Leu1878Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,613,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ADAMTS9
NM_182920.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.95

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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.872

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ADAMTS9	NM_182920.2 linkuse as main transcript	c.5632C>G	p.Leu1878Val	missense_variant	38/40	ENST00000498707.5	NP_891550.1
ADAMTS9	NM_001318781.2 linkuse as main transcript	c.5548C>G	p.Leu1850Val	missense_variant	37/39		NP_001305710.1
ADAMTS9	XR_007095711.1 linkuse as main transcript	n.5891C>G		non_coding_transcript_exon_variant	37/40
ADAMTS9	XR_245151.1 linkuse as main transcript	n.5975C>G		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.5632C>G	p.Leu1878Val	missense_variant	38/40	1	NM_182920.2	ENSP00000418735	P1	Q9P2N4-3
ADAMTS9	ENST00000295903.8 linkuse as main transcript	c.5548C>G	p.Leu1850Val	missense_variant	37/39	1		ENSP00000295903		Q9P2N4-4
ADAMTS9	ENST00000481060.2 linkuse as main transcript	c.2800C>G	p.Leu934Val	missense_variant	19/21	2		ENSP00000417521
ADAMTS9	ENST00000467257.5 linkuse as main transcript	c.34C>G	p.Leu12Val	missense_variant, NMD_transcript_variant	2/5	5		ENSP00000478086

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251318

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135818

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461792

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000247

AC:

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 13, 2023

The c.5632C>G (p.L1878V) alteration is located in exon 38 (coding exon 38) of the ADAMTS9 gene. This alteration results from a C to G substitution at nucleotide position 5632, causing the leucine (L) at amino acid position 1878 to be replaced by a valine (V). 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

0.26

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.26

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.97

D;D

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Benign

-0.43

MutationAssessor

Uncertain

2.9

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-2.4

N;N

REVEL

Uncertain

0.46

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.72

MutPred

0.85

Loss of loop (P = 0.0804);.;

MVP

0.66

MPC

0.75

ClinPred

0.98

GERP RS

5.2

Varity_R

0.71

gMVP

0.75

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over