chr4-72488177-T-C

Variant names:

• chr4-72488177-T-C
• rs788919
• NM_014243.3:c.504+60301A>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+60301A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 151,762 control chromosomes in the GnomAD database, including 5,539 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 0.27 (5539 hom., cov: 31)
• Consequence: ADAMTS3 NM_014243.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.176
• Publications: 2 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.296 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014243.3. 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
	ADAMTS3	NM_014243.3	MANE Select	c.504+60301A>G		intron	N/A	NP_055058.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS3	ENST00000286657.10	TSL:1 MANE Select	c.504+60301A>G		intron	N/A	ENSP00000286657.4
	ADAMTS3	ENST00000505193.1	TSL:2	n.462-45961A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40608 AN: 151642 Hom.: 5532 Cov.: 31

Gnomad AFR AF: 0.300

Gnomad AMI AF: 0.445

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.235

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.203

Gnomad FIN AF: 0.240

Gnomad MID AF: 0.322

Gnomad NFE AF: 0.259

Gnomad OTH AF: 0.275

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

GnomAD4 genome AF: 0.268 AC: 40646 AN: 151762 Hom.: 5539 Cov.: 31 AF XY: 0.268 AC XY: 19853 AN XY: 74174

African (AFR) AF: 0.300 AC: 12430 AN: 41434

American (AMR) AF: 0.268 AC: 4086 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.235 AC: 813 AN: 3456

East Asian (EAS) AF: 0.229 AC: 1181 AN: 5168

South Asian (SAS) AF: 0.204 AC: 981 AN: 4820

European-Finnish (FIN) AF: 0.240 AC: 2532 AN: 10560

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.259 AC: 17547 AN: 67794

Other (OTH) AF: 0.273 AC: 575 AN: 2106

Alfa AF: 0.270 Hom.: 7552

Bravo AF: 0.274

Asia WGS AF: 0.225 AC: 782 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	8.5
DANN	Benign	0.68
PhyloP100		-0.18
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: rs788919; hg19: chr4-73353894;