rs547548078

Variant names:

• chr5-179345235-G-A
• rs547548078
• NM_014244.5:c.94C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. 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. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P32L) has been classified as Uncertain significance.

• 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:2 B:4
• Conservation: PhyloP100: 2.05
• Publications: 1 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), Genomics England PanelApp, Orphanet, G2P, PanelApp Australia, Illumina

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• 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 VariationId is 291050.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS2	NM_014244.5	MANE Select	c.94C>T	p.Pro32Ser	missense	Exon 1 of 22	NP_055059.2
	ADAMTS2	NM_021599.4		c.94C>T	p.Pro32Ser	missense	Exon 1 of 11	NP_067610.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS2	ENST00000251582.12	TSL:1 MANE Select	c.94C>T	p.Pro32Ser	missense	Exon 1 of 22	ENSP00000251582.7
	ADAMTS2	ENST00000274609.5	TSL:1	c.94C>T	p.Pro32Ser	missense	Exon 1 of 11	ENSP00000274609.5
	ADAMTS2	ENST00000518335.3	TSL:3	c.94C>T	p.Pro32Ser	missense	Exon 1 of 21	ENSP00000489888.2

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

GnomAD2 exomes AF: 0.00 AC: 0 AN: 946 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

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

African (AFR) AF: 0.00466 AC: 91 AN: 19526

American (AMR) AF: 0.000555 AC: 3 AN: 5402

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9798

East Asian (EAS) AF: 0.00 AC: 0 AN: 15876

South Asian (SAS) AF: 0.00 AC: 0 AN: 19120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2486

European-Non Finnish (NFE) AF: 0.00000344 AC: 3 AN: 870998

Other (OTH) AF: 0.000243 AC: 9 AN: 37026

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

African (AFR) AF: 0.00412 AC: 167 AN: 40486

American (AMR) AF: 0.000668 AC: 10 AN: 14978

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3426

East Asian (EAS) AF: 0.00 AC: 0 AN: 4982

South Asian (SAS) AF: 0.00 AC: 0 AN: 4728

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000150 AC: 1 AN: 66732

Other (OTH) AF: 0.000488 AC: 1 AN: 2050

Alfa AF: 0.000783 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Ehlers-Danlos syndrome, dermatosparaxis type (2)
-	1	1	not provided (2)
-	-	1	ADAMTS2-related disorder (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		2.0
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.19	N
REVEL	Benign	0.047
Sift	Benign	0.13	T
Sift4G	Benign	0.60	T
Polyphen		0.12	B
Vest4		0.30
MutPred		0.36		Gain of phosphorylation at P32 (P = 0.0104)
MVP		0.58
MPC		0.41
ClinPred		0.38	T
GERP RS		1.8
PromoterAI		0.031	Neutral
Varity_R		0.036
gMVP		0.32
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs547548078; hg19: chr5-178772236;