4-72283534-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_014243.3(ADAMTS3):c.3220T>C(p.Ser1074Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00412 in 1,614,070 control chromosomes in the GnomAD database, including 213 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.021 (112 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (101 hom.)
• Consequence: ADAMTS3 NM_014243.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.67

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020766258).
• BP6: Variant 4-72283534-A-G is Benign according to our data. Variant chr4-72283534-A-G is described in ClinVar as [Benign]. Clinvar id is 716108.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-72283534-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0714 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS3	NM_014243.3	c.3220T>C	p.Ser1074Pro	missense_variant	22/22	ENST00000286657.10
ADAMTS3	XM_011532421.2	c.3163T>C	p.Ser1055Pro	missense_variant	22/22
ADAMTS3	XM_011532422.4	c.3136T>C	p.Ser1046Pro	missense_variant	22/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS3	ENST00000286657.10	c.3220T>C	p.Ser1074Pro	missense_variant	22/22	1	NM_014243.3	P1

Frequencies

GnomAD3 genomes AF: 0.0211 AC: 3208 AN: 152132 Hom.: 112 Cov.: 32

Gnomad AFR AF: 0.0735

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00740

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00555 AC: 1393 AN: 251202 Hom.: 39 AF XY: 0.00403 AC XY: 547 AN XY: 135768

Gnomad AFR exome AF: 0.0732

Gnomad AMR exome AF: 0.00370

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000751

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00235 AC: 3433 AN: 1461820 Hom.: 101 Cov.: 31 AF XY: 0.00210 AC XY: 1527 AN XY: 727220

Gnomad4 AFR exome AF: 0.0773

Gnomad4 AMR exome AF: 0.00411

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000638

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000239

Gnomad4 OTH exome AF: 0.00500

GnomAD4 genome AF: 0.0211 AC: 3220 AN: 152250 Hom.: 112 Cov.: 32 AF XY: 0.0201 AC XY: 1498 AN XY: 74438

Gnomad4 AFR AF: 0.0735

Gnomad4 AMR AF: 0.00739

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00424 Hom.: 38

Bravo AF: 0.0242

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0658 AC: 290

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00693 AC: 841

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	0.073
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	16
Dann	Benign	0.95
DEOGEN2	Benign	0.0085	T;T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.76	D
MetaRNN	Benign	0.0021	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.1	N;.
REVEL	Benign	0.058
Sift	Benign	0.22	T;.
Sift4G	Benign	0.27	T;T
Polyphen		0.0	B;B
Vest4		0.081
MVP		0.60
MPC		0.15
ClinPred		0.012	T
GERP RS		4.3
Varity_R		0.10
gMVP		0.49

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: rs35864003; hg19: chr4-73149251;