3-64522237-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_182920.2(ADAMTS9):c.5742A>G(p.Lys1914=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00898 in 1,613,998 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0093 (72 hom.)
• Consequence: ADAMTS9 NM_182920.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0700

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 3-64522237-T-C is Benign according to our data. Variant chr3-64522237-T-C is described in ClinVar as [Benign]. Clinvar id is 789164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.07 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS9	NM_182920.2	c.5742A>G	p.Lys1914=	synonymous_variant	39/40	ENST00000498707.5
ADAMTS9	NM_001318781.2	c.5658A>G	p.Lys1886=	synonymous_variant	38/39
ADAMTS9	XR_007095711.1	n.6001A>G		non_coding_transcript_exon_variant	38/40
ADAMTS9	XR_245151.1	n.6085A>G		non_coding_transcript_exon_variant	39/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS9	ENST00000498707.5	c.5742A>G	p.Lys1914=	synonymous_variant	39/40	1	NM_182920.2	P1

Frequencies

GnomAD3 genomes AF: 0.00544 AC: 829 AN: 152250 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00963

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00596 AC: 1498 AN: 251372 Hom.: 14 AF XY: 0.00580 AC XY: 788 AN XY: 135844

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.00284

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00160

Gnomad FIN exome AF: 0.00365

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.00521

GnomAD4 exome AF: 0.00935 AC: 13664 AN: 1461630 Hom.: 72 Cov.: 30 AF XY: 0.00908 AC XY: 6601 AN XY: 727128

Gnomad4 AFR exome AF: 0.00200

Gnomad4 AMR exome AF: 0.00284

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00165

Gnomad4 FIN exome AF: 0.00417

Gnomad4 NFE exome AF: 0.0113

Gnomad4 OTH exome AF: 0.00820

GnomAD4 genome AF: 0.00544 AC: 829 AN: 152368 Hom.: 3 Cov.: 33 AF XY: 0.00486 AC XY: 362 AN XY: 74528

Gnomad4 AFR AF: 0.00180

Gnomad4 AMR AF: 0.00346

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00245

Gnomad4 NFE AF: 0.00963

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00716 Hom.: 1

Bravo AF: 0.00560

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ADAMTS9-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 28, 2019

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

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
Cadd	Benign	2.3
Dann	Benign	0.51

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: rs61754854; hg19: chr3-64507913; COSMIC: COSV55789727;