rs4694121

Variant names:

• chr4-72300777-T-C
• rs4694121
• NM_014243.3:c.2425-2335A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014243.3(ADAMTS3):​c.2425-2335A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 152,076 control chromosomes in the GnomAD database, including 3,495 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.20 (3495 hom., cov: 32)
• Consequence: ADAMTS3 NM_014243.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.849
• Publications: 4 publications found

Genes affected

ADAMTS3 (HGNC:219): (ADAM metallopeptidase with thrombospondin type 1 motif 3) 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. The encoded preproprotein is proteolytically processed to generate the mature protease. This protease, a member of the procollagen aminopropeptidase subfamily of proteins, may play a role in the processing of type II fibrillar collagen in articular cartilage. [provided by RefSeq, Feb 2016]

ADAMTS3 Gene-Disease associations (from GenCC):

• hennekam lymphangiectasia-lymphedema syndrome 3

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Hennekam syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.45 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS3	NM_014243.3	c.2425-2335A>G		intron_variant	Intron 17 of 21	ENST00000286657.10	NP_055058.2
ADAMTS3	XM_011532421.2	c.2368-2335A>G		intron_variant	Intron 17 of 21		XP_011530723.1
ADAMTS3	XM_011532422.4	c.2341-2335A>G		intron_variant	Intron 17 of 21		XP_011530724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS3	ENST00000286657.10	c.2425-2335A>G		intron_variant	Intron 17 of 21	1	NM_014243.3	ENSP00000286657.4
ADAMTS3	ENST00000511274.1	n.648-2335A>G		intron_variant	Intron 5 of 5	1

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29763 AN: 151960 Hom.: 3483 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.0998

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.249

Gnomad EAS AF: 0.466

Gnomad SAS AF: 0.378

Gnomad FIN AF: 0.230

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.194

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.196 AC: 29802 AN: 152076 Hom.: 3495 Cov.: 32 AF XY: 0.205 AC XY: 15263 AN XY: 74326

African (AFR) AF: 0.101 AC: 4187 AN: 41500

American (AMR) AF: 0.296 AC: 4521 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 863 AN: 3470

East Asian (EAS) AF: 0.466 AC: 2394 AN: 5140

South Asian (SAS) AF: 0.378 AC: 1822 AN: 4818

European-Finnish (FIN) AF: 0.230 AC: 2436 AN: 10584

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.191 AC: 13011 AN: 68002

Other (OTH) AF: 0.200 AC: 421 AN: 2108

Alfa AF: 0.182 Hom.: 477

Bravo AF: 0.199

Asia WGS AF: 0.399 AC: 1385 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.44
DANN	Benign	0.28
PhyloP100		-0.85
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: rs4694121; hg19: chr4-73166494;