rs79330641

Variant names:

• chr5-179122718-G-A
• rs79330641
• NM_014244.5:c.3014C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-179122718-G-A
• chr5-179122718-G-C
• chr5-179122718-G-T

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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
• Publications: 7 publications found

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]

ADAMTS2 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome, dermatosparaxis type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Illumina, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014244.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS2	NM_014244.5	MANE Select	c.3014C>T	p.Ala1005Val	missense	Exon 20 of 22	NP_055059.2	O95450-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS2	ENST00000251582.12	TSL:1 MANE Select	c.3014C>T	p.Ala1005Val	missense	Exon 20 of 22	ENSP00000251582.7	O95450-1
	ADAMTS2	ENST00000957641.1		c.2957C>T	p.Ala986Val	missense	Exon 20 of 22	ENSP00000627700.1
	ADAMTS2	ENST00000518335.3	TSL:3	c.3014C>T	p.Ala1005Val	missense	Exon 20 of 21	ENSP00000489888.2	A0A1B0GTY3

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

GnomAD2 exomes AF: 0.00161 AC: 253 AN: 157232 AF XY: 0.00126

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 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

African (AFR) AF: 0.0249 AC: 788 AN: 31702

American (AMR) AF: 0.00159 AC: 57 AN: 35862

Ashkenazi Jewish (ASJ) AF: 0.000159 AC: 4 AN: 25170

East Asian (EAS) AF: 0.00 AC: 0 AN: 35850

South Asian (SAS) AF: 0.000113 AC: 9 AN: 79336

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48320

Middle Eastern (MID) AF: 0.00264 AC: 15 AN: 5690

European-Non Finnish (NFE) AF: 0.000112 AC: 121 AN: 1080036

Other (OTH) AF: 0.00229 AC: 133 AN: 58086

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

African (AFR) AF: 0.0228 AC: 947 AN: 41572

American (AMR) AF: 0.00300 AC: 46 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68036

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.00119 Hom.: 5

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Ehlers-Danlos syndrome, dermatosparaxis type (3)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.17	N
PhyloP100		-0.15
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
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs79330641; hg19: chr5-178549719; COSMIC: COSV52366657; COSMIC: COSV52366657;