chr3-64522237-T-C

Variant names:

• chr3-64522237-T-C
• rs61754854
• NM_182920.2:c.5742A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4 BP6_Moderate BP7 BS2

The NM_182920.2(ADAMTS9):​c.5742A>G​(p.Lys1914Lys) 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, single submitter B:2
• Conservation: PhyloP100: 0.0700
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• nephronophthisis 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• ciliopathy

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.28).
• BP6: Variant 3-64522237-T-C is Benign according to our data. Variant chr3-64522237-T-C is described in ClinVar as Benign. ClinVar VariationId is 789164.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.07 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182920.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS9	NM_182920.2	MANE Select	c.5742A>G	p.Lys1914Lys	synonymous	Exon 39 of 40	NP_891550.1	Q9P2N4-3
	ADAMTS9	NM_001318781.2		c.5658A>G	p.Lys1886Lys	synonymous	Exon 38 of 39	NP_001305710.1	Q9P2N4-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS9	ENST00000498707.5	TSL:1 MANE Select	c.5742A>G	p.Lys1914Lys	synonymous	Exon 39 of 40	ENSP00000418735.1	Q9P2N4-3
	ADAMTS9	ENST00000295903.8	TSL:1	c.5658A>G	p.Lys1886Lys	synonymous	Exon 38 of 39	ENSP00000295903.4	Q9P2N4-4
	ADAMTS9	ENST00000481060.2	TSL:2	c.2907A>G	p.Lys969Lys	synonymous	Exon 20 of 21	ENSP00000417521.1	H0Y859

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

GnomAD2 exomes AF: 0.00596 AC: 1498 AN: 251372 AF XY: 0.00580

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 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

African (AFR) AF: 0.00200 AC: 67 AN: 33462

American (AMR) AF: 0.00284 AC: 127 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.000306 AC: 8 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00165 AC: 142 AN: 86252

European-Finnish (FIN) AF: 0.00417 AC: 223 AN: 53416

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0113 AC: 12595 AN: 1111838

Other (OTH) AF: 0.00820 AC: 495 AN: 60382

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

African (AFR) AF: 0.00180 AC: 75 AN: 41600

American (AMR) AF: 0.00346 AC: 53 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.00245 AC: 26 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00963 AC: 655 AN: 68026

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00716 Hom.: 1

Bravo AF: 0.00560

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	ADAMTS9-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	2.3
DANN	Benign	0.51
PhyloP100		0.070
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

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