3-64541041-G-C

Variant names:

• chr3-64541041-G-C
• rs3796384
• NM_182920.2:c.5521+54C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182920.2(ADAMTS9):​c.5521+54C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.79 in 1,604,902 control chromosomes in the GnomAD database, including 520,803 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (35793 hom., cov: 33)
  • Exomes 𝑓: 0.81 (485010 hom.)
• Consequence: ADAMTS9 NM_182920.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0490
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 3-64541041-G-C is Benign according to our data. Variant chr3-64541041-G-C is described in ClinVar as Benign. ClinVar VariationId is 1247158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.844 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS9	NM_182920.2	MANE Select	c.5521+54C>G		intron	N/A	NP_891550.1
	ADAMTS9	NM_001318781.2		c.5437+54C>G		intron	N/A	NP_001305710.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS9	ENST00000498707.5	TSL:1 MANE Select	c.5521+54C>G		intron	N/A	ENSP00000418735.1
	ADAMTS9	ENST00000295903.8	TSL:1	c.5437+54C>G		intron	N/A	ENSP00000295903.4
	ADAMTS9	ENST00000481060.2	TSL:2	c.2686+54C>G		intron	N/A	ENSP00000417521.1

Frequencies

GnomAD3 genomes AF: 0.642 AC: 97542 AN: 151976 Hom.: 35792 Cov.: 33

Gnomad AFR AF: 0.304

Gnomad AMI AF: 0.828

Gnomad AMR AF: 0.540

Gnomad ASJ AF: 0.866

Gnomad EAS AF: 0.406

Gnomad SAS AF: 0.766

Gnomad FIN AF: 0.732

Gnomad MID AF: 0.788

Gnomad NFE AF: 0.850

Gnomad OTH AF: 0.666

GnomAD4 exome AF: 0.805 AC: 1169564 AN: 1452808 Hom.: 485010 AF XY: 0.809 AC XY: 583651 AN XY: 721794

African (AFR) AF: 0.288 AC: 9548 AN: 33174

American (AMR) AF: 0.406 AC: 17923 AN: 44122

Ashkenazi Jewish (ASJ) AF: 0.849 AC: 21778 AN: 25656

East Asian (EAS) AF: 0.375 AC: 14842 AN: 39586

South Asian (SAS) AF: 0.793 AC: 67409 AN: 85040

European-Finnish (FIN) AF: 0.752 AC: 39870 AN: 53028

Middle Eastern (MID) AF: 0.819 AC: 4677 AN: 5714

European-Non Finnish (NFE) AF: 0.856 AC: 946933 AN: 1106514

Other (OTH) AF: 0.777 AC: 46584 AN: 59974

GnomAD4 genome AF: 0.641 AC: 97551 AN: 152094 Hom.: 35793 Cov.: 33 AF XY: 0.634 AC XY: 47144 AN XY: 74346

African (AFR) AF: 0.304 AC: 12596 AN: 41478

American (AMR) AF: 0.539 AC: 8237 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.866 AC: 3002 AN: 3468

East Asian (EAS) AF: 0.406 AC: 2092 AN: 5156

South Asian (SAS) AF: 0.767 AC: 3692 AN: 4816

European-Finnish (FIN) AF: 0.732 AC: 7725 AN: 10558

Middle Eastern (MID) AF: 0.793 AC: 233 AN: 294

European-Non Finnish (NFE) AF: 0.850 AC: 57816 AN: 68018

Other (OTH) AF: 0.664 AC: 1403 AN: 2112

Alfa AF: 0.735 Hom.: 5519

Bravo AF: 0.604

Asia WGS AF: 0.565 AC: 1968 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

May 08, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.4
DANN	Benign	0.53
PhyloP100		0.049
Mutation Taster		=100/0	polymorphism (auto)

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: rs3796384; hg19: chr3-64526717; COSMIC: COSV55781666; COSMIC: COSV55781666;