rs4694123

Variant names:

• chr4-72522071-T-C
• rs4694123
• NM_014243.3:c.504+26407A>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.504+26407A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 152,026 control chromosomes in the GnomAD database, including 5,065 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 0.25 (5065 hom., cov: 32)
• Consequence: ADAMTS3 NM_014243.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.824
• Publications: 1 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=-0.48).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS3	NM_014243.3	c.504+26407A>G		intron_variant	Intron 3 of 21	ENST00000286657.10	NP_055058.2
ADAMTS3	XM_011532421.2	c.447+26407A>G		intron_variant	Intron 3 of 21		XP_011530723.1
ADAMTS3	XM_011532422.4	c.420+26407A>G		intron_variant	Intron 3 of 21		XP_011530724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS3	ENST00000286657.10	c.504+26407A>G		intron_variant	Intron 3 of 21	1	NM_014243.3	ENSP00000286657.4
ADAMTS3	ENST00000505193.1	n.461+26407A>G		intron_variant	Intron 3 of 3	2

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38550 AN: 151908 Hom.: 5057 Cov.: 32

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.446

Gnomad AMR AF: 0.275

Gnomad ASJ AF: 0.276

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.261

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.280

Gnomad OTH AF: 0.263

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

GnomAD4 genome AF: 0.254 AC: 38573 AN: 152026 Hom.: 5065 Cov.: 32 AF XY: 0.254 AC XY: 18878 AN XY: 74280

African (AFR) AF: 0.199 AC: 8267 AN: 41494

American (AMR) AF: 0.275 AC: 4200 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.276 AC: 956 AN: 3464

East Asian (EAS) AF: 0.229 AC: 1184 AN: 5166

South Asian (SAS) AF: 0.240 AC: 1155 AN: 4812

European-Finnish (FIN) AF: 0.261 AC: 2757 AN: 10560

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.280 AC: 18998 AN: 67958

Other (OTH) AF: 0.261 AC: 550 AN: 2110

Alfa AF: 0.265 Hom.: 1084

Bravo AF: 0.255

Asia WGS AF: 0.236 AC: 820 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	16
DANN	Benign	0.76
PhyloP100		0.82
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: rs4694123; hg19: chr4-73387788;