4-72283311-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014243.3(ADAMTS3):c.3443C>T(p.Pro1148Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,613,984 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (28 hom., cov: 32)
  • Exomes 𝑓: 0.00095 (19 hom.)
• Consequence: ADAMTS3 NM_014243.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.22

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004003465).
• BP6: Variant 4-72283311-G-A is Benign according to our data. Variant chr4-72283311-G-A is described in ClinVar as [Benign]. Clinvar id is 787029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0093 (1415/152200) while in subpopulation AFR AF= 0.0321 (1334/41520). AF 95% confidence interval is 0.0307. There are 28 homozygotes in gnomad4. There are 648 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS3	NM_014243.3	c.3443C>T	p.Pro1148Leu	missense_variant	22/22	ENST00000286657.10
ADAMTS3	XM_011532421.2	c.3386C>T	p.Pro1129Leu	missense_variant	22/22
ADAMTS3	XM_011532422.4	c.3359C>T	p.Pro1120Leu	missense_variant	22/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS3	ENST00000286657.10	c.3443C>T	p.Pro1148Leu	missense_variant	22/22	1	NM_014243.3	P1

Frequencies

GnomAD3 genomes AF: 0.00929 AC: 1413 AN: 152082 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.0322

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00909

GnomAD3 exomes AF: 0.00225 AC: 565 AN: 250758 Hom.: 7 AF XY: 0.00168 AC XY: 228 AN XY: 135476

Gnomad AFR exome AF: 0.0320

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000707

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000950 AC: 1388 AN: 1461784 Hom.: 19 Cov.: 31 AF XY: 0.000831 AC XY: 604 AN XY: 727196

Gnomad4 AFR exome AF: 0.0356

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.00187

GnomAD4 genome AF: 0.00930 AC: 1415 AN: 152200 Hom.: 28 Cov.: 32 AF XY: 0.00871 AC XY: 648 AN XY: 74418

Gnomad4 AFR AF: 0.0321

Gnomad4 AMR AF: 0.00334

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00141 Hom.: 5

Bravo AF: 0.0106

ESP6500AA AF: 0.0272 AC: 120

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00264 AC: 321

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ADAMTS3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 19, 2019

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

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	6.8
Dann	Uncertain	0.98
DEOGEN2	Benign	0.040	T;T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.14	N
MetaRNN	Benign	0.0040	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.048
Sift	Benign	0.20	T;.
Sift4G	Benign	0.12	T;T
Polyphen		0.0050	B;B
Vest4		0.067
MVP		0.62
MPC		0.12
ClinPred		0.0038	T
GERP RS		2.5
Varity_R		0.031
gMVP		0.24

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: rs35780102; hg19: chr4-73149028;