rs146222244

Positions:

• chr5-179132248-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014244.5(ADAMTS2):​c.2272G>A​(p.Ala758Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000622 in 1,614,090 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (0 hom.)
• Consequence: ADAMTS2 NM_014244.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5 B:1
• Conservation: PhyloP100: -0.470

Genes affected

ADAMTS2 (HGNC:218): (ADAM metallopeptidase with thrombospondin type 1 motif 2) 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 procollagen N-proteinase. This proteinase excises the N-propeptide of the fibrillar procollagens types I-III and type V. Mutations in this gene cause Ehlers-Danlos syndrome type VIIC, a recessively inherited connective-tissue disorder. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.011641502).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS2	NM_014244.5	c.2272G>A	p.Ala758Thr	missense_variant	15/22	ENST00000251582.12
ADAMTS2	XM_047417895.1	c.1777G>A	p.Ala593Thr	missense_variant	14/21
ADAMTS2	XM_047417896.1	c.1390G>A	p.Ala464Thr	missense_variant	13/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.2272G>A	p.Ala758Thr	missense_variant	15/22	1	NM_014244.5	P2
ADAMTS2	ENST00000518335.3	c.2272G>A	p.Ala758Thr	missense_variant	15/21	3		A2
ADAMTS2	ENST00000698889.1	c.2272G>A	p.Ala758Thr	missense_variant, NMD_transcript_variant	15/21

Frequencies

GnomAD3 genomes AF: 0.000526 AC: 80 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000434 AC: 109 AN: 251312 Hom.: 0 AF XY: 0.000486 AC XY: 66 AN XY: 135892

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000555

Gnomad NFE exome AF: 0.000642

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000632 AC: 924 AN: 1461778 Hom.: 0 Cov.: 32 AF XY: 0.000635 AC XY: 462 AN XY: 727184

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.000524

Gnomad4 NFE exome AF: 0.000741

Gnomad4 OTH exome AF: 0.000547

GnomAD4 genome AF: 0.000525 AC: 80 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33 AN XY: 74474

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000942

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000691 Hom.: 1

Bravo AF: 0.000529

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000436 AC: 53

EpiCase AF: 0.000654

EpiControl AF: 0.00101

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 05, 2023	BP4 -

Ehlers-Danlos syndrome, dermatosparaxis type Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 02, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 07, 2022	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 758 of the ADAMTS2 protein (p.Ala758Thr). This variant is present in population databases (rs146222244, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ADAMTS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 450954). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	12
DANN	Benign	0.88
DEOGEN2	Benign	0.16	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.063	N
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.89	L;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.0	N;.
REVEL	Benign	0.071
Sift	Benign	0.40	T;.
Sift4G	Benign	0.41	T;.
Polyphen		0.050	B;.
Vest4		0.10
MVP		0.28
MPC		0.40
ClinPred		0.018	T
GERP RS		-6.5
Varity_R		0.057
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs146222244; hg19: chr5-178559249;