4-72290961-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_014243.3(ADAMTS3):c.2825A>G(p.Asn942Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00333 in 1,613,996 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (16 hom.)
• Consequence: ADAMTS3 NM_014243.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.23

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008250326).
• BP6: Variant 4-72290961-T-C is Benign according to our data. Variant chr4-72290961-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 717678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-72290961-T-C is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS3	NM_014243.3	c.2825A>G	p.Asn942Ser	missense_variant	20/22	ENST00000286657.10
ADAMTS3	XM_011532421.2	c.2768A>G	p.Asn923Ser	missense_variant	20/22
ADAMTS3	XM_011532422.4	c.2741A>G	p.Asn914Ser	missense_variant	20/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS3	ENST00000286657.10	c.2825A>G	p.Asn942Ser	missense_variant	20/22	1	NM_014243.3	P1

Frequencies

GnomAD3 genomes AF: 0.00278 AC: 423 AN: 152112 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00463

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00244 AC: 613 AN: 251000 Hom.: 2 AF XY: 0.00240 AC XY: 326 AN XY: 135636

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00289

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.000882

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00366

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00338 AC: 4948 AN: 1461766 Hom.: 16 Cov.: 31 AF XY: 0.00336 AC XY: 2440 AN XY: 727184

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.00282

Gnomad4 ASJ exome AF: 0.00199

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00117

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.00400

Gnomad4 OTH exome AF: 0.00233

GnomAD4 genome AF: 0.00277 AC: 422 AN: 152230 Hom.: 1 Cov.: 32 AF XY: 0.00293 AC XY: 218 AN XY: 74440

Gnomad4 AFR AF: 0.000578

Gnomad4 AMR AF: 0.00406

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00463

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00397 Hom.: 0

Bravo AF: 0.00261

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00360 AC: 31

ExAC AF: 0.00245 AC: 297

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00513

EpiControl AF: 0.00450

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ADAMTS3: BP4, BS2 -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

ADAMTS3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 19, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	17
Dann	Benign	0.93
DEOGEN2	Benign	0.055	T;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.0083	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.82	L;L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.9	N;.
REVEL	Benign	0.13
Sift	Benign	0.12	T;.
Sift4G	Benign	0.063	T;T
Polyphen		0.065	B;B
Vest4		0.34
MVP		0.66
MPC		0.099
ClinPred		0.018	T
GERP RS		4.2
Varity_R		0.056
gMVP		0.15

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

LitVar

Other links and lift over

dbSNP: rs143166648; hg19: chr4-73156678;