rs547548078

Positions:

• chr5-179345235-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_014244.5(ADAMTS2):​c.94C>T​(p.Pro32Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000249 in 1,143,624 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: ADAMTS2 NM_014244.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 2.05

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 Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.025395364).
• BP6: Variant 5-179345235-G-A is Benign according to our data. Variant chr5-179345235-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 291050.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00121 (179/147982) while in subpopulation AFR AF= 0.00412 (167/40486). AF 95% confidence interval is 0.00361. There are 1 homozygotes in gnomad4. There are 74 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS2	NM_014244.5	c.94C>T	p.Pro32Ser	missense_variant	1/22	ENST00000251582.12	NP_055059.2
ADAMTS2	NM_021599.4	c.94C>T	p.Pro32Ser	missense_variant	1/11		NP_067610.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.94C>T	p.Pro32Ser	missense_variant	1/22	1	NM_014244.5	ENSP00000251582	P2
ADAMTS2	ENST00000274609.5	c.94C>T	p.Pro32Ser	missense_variant	1/11	1		ENSP00000274609
ADAMTS2	ENST00000518335.3	c.94C>T	p.Pro32Ser	missense_variant	1/21	3		ENSP00000489888	A2
ADAMTS2	ENST00000698889.1	c.94C>T	p.Pro32Ser	missense_variant, NMD_transcript_variant	1/21			ENSP00000514008

Frequencies

GnomAD3 genomes AF: 0.00121 AC: 179 AN: 147880 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00414

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000669

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000150

Gnomad OTH AF: 0.000493

GnomAD4 exome AF: 0.000106 AC: 106 AN: 995642 Hom.: 0 Cov.: 30 AF XY: 0.000124 AC XY: 59 AN XY: 475212

Gnomad4 AFR exome AF: 0.00466

Gnomad4 AMR exome AF: 0.000555

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000344

Gnomad4 OTH exome AF: 0.000243

GnomAD4 genome AF: 0.00121 AC: 179 AN: 147982 Hom.: 1 Cov.: 33 AF XY: 0.00103 AC XY: 74 AN XY: 72144

Gnomad4 AFR AF: 0.00412

Gnomad4 AMR AF: 0.000668

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000150

Gnomad4 OTH AF: 0.000488

Alfa AF: 0.000783 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 12, 2016	- -

Ehlers-Danlos syndrome, dermatosparaxis type Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 20, 2020	- -

ADAMTS2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 09, 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	0.10
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T;.;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.48	N
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.025	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.;N
MutationTaster	Benign	0.94	N;N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.19	N;.;N
REVEL	Benign	0.047
Sift	Benign	0.13	T;.;T
Sift4G	Benign	0.60	T;.;T
Polyphen		0.12	B;.;P
Vest4		0.30
MutPred		0.36		Gain of phosphorylation at P32 (P = 0.0104);Gain of phosphorylation at P32 (P = 0.0104);Gain of phosphorylation at P32 (P = 0.0104);
MVP		0.58
MPC		0.41
ClinPred		0.38	T
GERP RS		1.8
Varity_R		0.036
gMVP		0.32

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: rs547548078; hg19: chr5-178772236;