1-161191082-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005099.6(ADAMTS4):c.*56A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,496,092 control chromosomes in the GnomAD database, including 18,294 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (1641 hom., cov: 33)
  • Exomes 𝑓: 0.15 (16653 hom.)
• Consequence: ADAMTS4 NM_005099.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.230

Genes affected

ADAMTS4 (HGNC:220): (ADAM metallopeptidase with thrombospondin type 1 motif 4) This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. Members of this 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. The enzyme encoded by this gene lacks a C-terminal TS motif. The encoded preproprotein is proteolytically processed to generate the mature protease. This protease is responsible for the degradation of aggrecan, a major proteoglycan of cartilage, and brevican, a brain-specific extracellular matrix protein. The expression of this gene is upregulated in arthritic disease and this may contribute to disease progression through the degradation of aggrecan. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 1-161191082-T-C is Benign according to our data. Variant chr1-161191082-T-C is described in ClinVar as [Benign]. Clinvar id is 769539.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.328 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS4	NM_005099.6	c.*56A>G		3_prime_UTR_variant	9/9	ENST00000367996.6
ADAMTS4	NM_001320336.3	c.2409A>G	p.Arg803=	synonymous_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS4	ENST00000367996.6	c.*56A>G		3_prime_UTR_variant	9/9	1	NM_005099.6	P1

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19731 AN: 152126 Hom.: 1643 Cov.: 33

Gnomad AFR AF: 0.0454

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.206

Gnomad ASJ AF: 0.174

Gnomad EAS AF: 0.341

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.133

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.145

Gnomad OTH AF: 0.135

GnomAD4 exome AF: 0.150 AC: 201028 AN: 1343846 Hom.: 16653 Cov.: 28 AF XY: 0.149 AC XY: 98063 AN XY: 657926

Gnomad4 AFR exome AF: 0.0362

Gnomad4 AMR exome AF: 0.246

Gnomad4 ASJ exome AF: 0.182

Gnomad4 EAS exome AF: 0.354

Gnomad4 SAS exome AF: 0.108

Gnomad4 FIN exome AF: 0.124

Gnomad4 NFE exome AF: 0.146

Gnomad4 OTH exome AF: 0.151

GnomAD4 genome AF: 0.130 AC: 19725 AN: 152246 Hom.: 1641 Cov.: 33 AF XY: 0.131 AC XY: 9748 AN XY: 74438

Gnomad4 AFR AF: 0.0453

Gnomad4 AMR AF: 0.206

Gnomad4 ASJ AF: 0.174

Gnomad4 EAS AF: 0.341

Gnomad4 SAS AF: 0.103

Gnomad4 FIN AF: 0.133

Gnomad4 NFE AF: 0.145

Gnomad4 OTH AF: 0.139

Alfa AF: 0.138 Hom.: 307

Bravo AF: 0.134

Asia WGS AF: 0.208 AC: 724 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	3.2
Dann	Benign	0.71

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: rs34884997; hg19: chr1-161160872; COSMIC: COSV63489289; COSMIC: COSV63489289;