Genetic Variant ADAMTS3:c.505-41877A>G (chr4-72456848-T-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_014243.3(ADAMTS3):c.505-41877A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00567 in 151,636 control chromosomes in the GnomAD database, including 4 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 0.0057 ( 4 hom., cov: 32)

Consequence

ADAMTS3
NM_014243.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.99

Publications

8 publications found

Variant links:

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

ADAMTS3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS3	NM_014243.3 link	c.505-41877A>G	intron_variant	Intron 3 of 21	ENST00000286657.10	NP_055058.2	O15072Q96AY5B7Z2U9
ADAMTS3	XM_011532421.2 link	c.448-41877A>G	intron_variant	Intron 3 of 21		XP_011530723.1
ADAMTS3	XM_011532422.4 link	c.421-41877A>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 link	c.505-41877A>G		intron_variant	Intron 3 of 21	1	NM_014243.3	ENSP00000286657.4		O15072
ADAMTS3	ENST00000505193.1 link	n.462-14632A>G		intron_variant	Intron 3 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.00566

AC:

858

AN:

151518

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00364

Gnomad ASJ

AF:

0.00577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.00481

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00955

Gnomad OTH

AF:

0.00433

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

GnomAD4 genome

AF:

0.00567

AC:

860

AN:

151636

Hom.:

Cov.:

AF XY:

0.00537

AC XY:

398

AN XY:

74104

show subpopulations

African (AFR)

AF:

0.00145

AC:

AN:

41456

American (AMR)

AF:

0.00363

AC:

AN:

15134

Ashkenazi Jewish (ASJ)

AF:

0.00577

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5104

South Asian (SAS)

AF:

0.00373

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00481

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00955

AC:

647

AN:

67740

Other (OTH)

AF:

0.00428

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

139

186

232

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00833

Hom.:

Bravo

AF:

0.00537

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

0.022

(source)

DANN

Benign

0.56

PhyloP100

-3.0

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over