3-64539229-A-G

Variant names:

• chr3-64539229-A-G
• NM_182920.2:c.5587T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_182920.2(ADAMTS9):​c.5587T>C​(p.Cys1863Arg) variant causes a missense change involving the alteration of a 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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADAMTS9 NM_182920.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.46

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS9	NM_182920.2	c.5587T>C	p.Cys1863Arg	missense_variant	Exon 37 of 40	ENST00000498707.5	NP_891550.1
ADAMTS9	NM_001318781.2	c.5503T>C	p.Cys1835Arg	missense_variant	Exon 36 of 39		NP_001305710.1
ADAMTS9	XR_007095711.1	n.5846T>C		non_coding_transcript_exon_variant	Exon 36 of 40
ADAMTS9	XR_245151.1	n.5930T>C		non_coding_transcript_exon_variant	Exon 37 of 41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS9	ENST00000498707.5	c.5587T>C	p.Cys1863Arg	missense_variant	Exon 37 of 40	1	NM_182920.2	ENSP00000418735.1
ADAMTS9	ENST00000295903.8	c.5503T>C	p.Cys1835Arg	missense_variant	Exon 36 of 39	1		ENSP00000295903.4
ADAMTS9	ENST00000481060.2	c.2752T>C	p.Cys918Arg	missense_variant	Exon 18 of 21	2		ENSP00000417521.1
ADAMTS9	ENST00000467257.5	n.-12T>C		upstream_gene_variant		5		ENSP00000478086.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5587T>C (p.C1863R) alteration is located in exon 37 (coding exon 37) of the ADAMTS9 gene. This alteration results from a T to C substitution at nucleotide position 5587, causing the cysteine (C) at amino acid position 1863 to be replaced by an arginine (R). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.9	M;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-9.8	D;D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.96		Gain of disorder (P = 0.0299);.;
MVP		0.76
MPC		1.0
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.97
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-64524905;