chr1-161191082-T-C

Variant names:

• chr1-161191082-T-C
• rs34884997
• NM_005099.6:c.*56A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001320336.3(ADAMTS4):​c.2409A>G​(p.Arg803Arg) variant causes a synonymous 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_001320336.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.230
• Publications: 11 publications found

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

Our verdict: Benign. The variant received -21 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 VariationId is 769539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.23 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.328 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001320336.3. 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
	ADAMTS4	NM_005099.6	MANE Select	c.*56A>G		3_prime_UTR	Exon 9 of 9	NP_005090.3
	ADAMTS4	NM_001320336.3		c.2409A>G	p.Arg803Arg	synonymous	Exon 9 of 9	NP_001307265.1	O75173-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS4	ENST00000367996.6	TSL:1 MANE Select	c.*56A>G		3_prime_UTR	Exon 9 of 9	ENSP00000356975.4	O75173-1
	ADAMTS4	ENST00000926274.1		c.*56A>G		3_prime_UTR	Exon 9 of 9	ENSP00000596333.1
	ADAMTS4	ENST00000926273.1		c.*56A>G		3_prime_UTR	Exon 10 of 10	ENSP00000596332.1

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

African (AFR) AF: 0.0362 AC: 1085 AN: 29942

American (AMR) AF: 0.246 AC: 7119 AN: 28928

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 3605 AN: 19806

East Asian (EAS) AF: 0.354 AC: 13714 AN: 38704

South Asian (SAS) AF: 0.108 AC: 7570 AN: 69854

European-Finnish (FIN) AF: 0.124 AC: 5167 AN: 41518

Middle Eastern (MID) AF: 0.165 AC: 661 AN: 4010

European-Non Finnish (NFE) AF: 0.146 AC: 153733 AN: 1055628

Other (OTH) AF: 0.151 AC: 8374 AN: 55456

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

African (AFR) AF: 0.0453 AC: 1881 AN: 41562

American (AMR) AF: 0.206 AC: 3146 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 603 AN: 3468

East Asian (EAS) AF: 0.341 AC: 1766 AN: 5176

South Asian (SAS) AF: 0.103 AC: 499 AN: 4830

European-Finnish (FIN) AF: 0.133 AC: 1413 AN: 10600

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.145 AC: 9885 AN: 67994

Other (OTH) AF: 0.139 AC: 294 AN: 2112

Alfa AF: 0.119 Hom.: 578

Bravo AF: 0.134

Asia WGS AF: 0.208 AC: 724 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.2
DANN	Benign	0.71
PhyloP100		-0.23
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: rs34884997; hg19: chr1-161160872; COSMIC: COSV63489289; COSMIC: COSV63489289;