3-64522245-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_182920.2(ADAMTS9):c.5734G>A(p.Val1912Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00203 in 1,614,032 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (2 hom.)
• Consequence: ADAMTS9 NM_182920.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.23

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011214286).
• BP6: Variant 3-64522245-C-T is Benign according to our data. Variant chr3-64522245-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1546394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS9	NM_182920.2	c.5734G>A	p.Val1912Ile	missense_variant	39/40	ENST00000498707.5
ADAMTS9	NM_001318781.2	c.5650G>A	p.Val1884Ile	missense_variant	38/39
ADAMTS9	XR_007095711.1	n.5993G>A		non_coding_transcript_exon_variant	38/40
ADAMTS9	XR_245151.1	n.6077G>A		non_coding_transcript_exon_variant	39/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS9	ENST00000498707.5	c.5734G>A	p.Val1912Ile	missense_variant	39/40	1	NM_182920.2	P1

Frequencies

GnomAD3 genomes AF: 0.00231 AC: 352 AN: 152242 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00273

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00583

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00241

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00196 AC: 493 AN: 251348 Hom.: 2 AF XY: 0.00198 AC XY: 269 AN XY: 135834

Gnomad AFR exome AF: 0.00283

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00531

Gnomad NFE exome AF: 0.00266

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.00200 AC: 2920 AN: 1461672 Hom.: 2 Cov.: 30 AF XY: 0.00199 AC XY: 1445 AN XY: 727140

Gnomad4 AFR exome AF: 0.00350

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00491

Gnomad4 NFE exome AF: 0.00218

Gnomad4 OTH exome AF: 0.00123

GnomAD4 genome AF: 0.00232 AC: 353 AN: 152360 Hom.: 0 Cov.: 33 AF XY: 0.00244 AC XY: 182 AN XY: 74518

Gnomad4 AFR AF: 0.00272

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00583

Gnomad4 NFE AF: 0.00243

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00202 Hom.: 1

Bravo AF: 0.00192

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00203 AC: 247

EpiCase AF: 0.00224

EpiControl AF: 0.00314

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ADAMTS9-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 09, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	0.21
Dann	Benign	0.61
DEOGEN2	Benign	0.052	T;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0083	N
LIST_S2	Benign	0.035	T;T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.050	N;N
REVEL	Benign	0.052
Sift	Benign	0.72	T;T
Sift4G	Benign	0.41	T;T
Polyphen		0.0	B;.
Vest4		0.075
MVP		0.13
MPC		0.15
ClinPred		0.0053	T
GERP RS		-10
Varity_R		0.036
gMVP		0.11

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

Other links and lift over

dbSNP: rs75938827; hg19: chr3-64507921; COSMIC: COSV99071205;