rs79330641

chr5-179122718-G-Achr5-179122718-G-Cchr5-179122718-G-T

Variant summary

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

The NM_014244.5(ADAMTS2):c.3014C>T(p.Ala1005Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,552,394 control chromosomes in the GnomAD database, including 23 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1005T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0067 (13 hom., cov: 33)
  • Exomes 𝑓: 0.00080 (10 hom.)
• Consequence: ADAMTS2 NM_014244.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.149

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041039586).
• BP6: Variant 5-179122718-G-A is Benign according to our data. Variant chr5-179122718-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 390199.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 = 0.00671 (1022/152342) while in subpopulation AFR AF= 0.0228 (947/41572). AF 95% confidence interval is 0.0216. There are 13 homozygotes in gnomad4. There are 482 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS2	NM_014244.5	c.3014C>T	p.Ala1005Val	missense_variant	20/22	ENST00000251582.12
ADAMTS2	XM_047417895.1	c.2519C>T	p.Ala840Val	missense_variant	19/21
ADAMTS2	XM_047417896.1	c.2132C>T	p.Ala711Val	missense_variant	18/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.3014C>T	p.Ala1005Val	missense_variant	20/22	1	NM_014244.5	P2
ADAMTS2	ENST00000518335.3	c.3014C>T	p.Ala1005Val	missense_variant	20/21	3		A2
ADAMTS2	ENST00000523450.1	n.122C>T		non_coding_transcript_exon_variant	1/3	2
ADAMTS2	ENST00000698889.1	c.*224C>T		3_prime_UTR_variant, NMD_transcript_variant	20/21

Frequencies

GnomAD3 genomes AF: 0.00671 AC: 1022 AN: 152224 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0228

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00307

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.00161 AC: 253 AN: 157232 Hom.: 3 AF XY: 0.00126 AC XY: 105 AN XY: 83122

Gnomad AFR exome AF: 0.0237

Gnomad AMR exome AF: 0.00109

Gnomad ASJ exome AF: 0.000235

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000874

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000148

Gnomad OTH exome AF: 0.000901

GnomAD4 exome AF: 0.000805 AC: 1127 AN: 1400052 Hom.: 10 Cov.: 31 AF XY: 0.000705 AC XY: 487 AN XY: 690698

Gnomad4 AFR exome AF: 0.0249

Gnomad4 AMR exome AF: 0.00159

Gnomad4 ASJ exome AF: 0.000159

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000113

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000112

Gnomad4 OTH exome AF: 0.00229

GnomAD4 genome AF: 0.00671 AC: 1022 AN: 152342 Hom.: 13 Cov.: 33 AF XY: 0.00647 AC XY: 482 AN XY: 74492

Gnomad4 AFR AF: 0.0228

Gnomad4 AMR AF: 0.00300

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.000903 Hom.: 4

Bravo AF: 0.00755

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0191 AC: 82

ESP6500EA AF: 0.000474 AC: 4

ExAC AF: 0.00101 AC: 108

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 02, 2019	- -

Ehlers-Danlos syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 01, 2019

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 14, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	12
Dann	Uncertain	0.98
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.057	N
MetaRNN	Benign	0.0041	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.17	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.8	N;.
REVEL	Benign	0.14
Sift	Benign	0.14	T;.
Sift4G	Benign	0.28	T;.
Polyphen		0.0070	B;.
Vest4		0.15
MVP		0.20
MPC		0.40
ClinPred		0.0053	T
GERP RS		-1.5
Varity_R		0.033
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs79330641; hg19: chr5-178549719; COSMIC: COSV52366657; COSMIC: COSV52366657;