5-179273003-G-T

Variant names:

• chr5-179273003-G-T
• rs76704342
• NM_014244.5:c.596C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014244.5(ADAMTS2):​c.596C>A​(p.Ala199Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,094 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ADAMTS2 NM_014244.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.147

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0872744).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS2	NM_014244.5	c.596C>A	p.Ala199Glu	missense_variant	Exon 3 of 22	ENST00000251582.12	NP_055059.2
ADAMTS2	NM_021599.4	c.596C>A	p.Ala199Glu	missense_variant	Exon 3 of 11		NP_067610.1
ADAMTS2	XM_047417895.1	c.101C>A	p.Ala34Glu	missense_variant	Exon 2 of 21		XP_047273851.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.596C>A	p.Ala199Glu	missense_variant	Exon 3 of 22	1	NM_014244.5	ENSP00000251582.7
ADAMTS2	ENST00000274609.5	c.596C>A	p.Ala199Glu	missense_variant	Exon 3 of 11	1		ENSP00000274609.5
ADAMTS2	ENST00000518335.3	c.596C>A	p.Ala199Glu	missense_variant	Exon 3 of 21	3		ENSP00000489888.2
ADAMTS2	ENST00000698889.1	n.596C>A		non_coding_transcript_exon_variant	Exon 3 of 21			ENSP00000514008.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251050 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135804

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461094 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 726882

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type Uncertain:1

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ADAMTS2 NM_014244.4 exon 3 p.Ala199Glu (c.596C>A): This variant has not been reported in the literature and is present in 0.003% (1/30614) of South Asian alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/5-178700004-G-T). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	3.4
DANN	Benign	0.64
DEOGEN2	Benign	0.067	T;.;.
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.024	N
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.087	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.83	L;.;L
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.1	N;.;N
REVEL	Benign	0.050
Sift	Benign	0.68	T;.;T
Sift4G	Benign	0.91	T;.;T
Polyphen		0.042	B;.;B
Vest4		0.27
MutPred		0.67		Gain of disorder (P = 0.0448);Gain of disorder (P = 0.0448);Gain of disorder (P = 0.0448);
MVP		0.35
MPC		0.48
ClinPred		0.034	T
GERP RS		1.2
Varity_R		0.055
gMVP		0.54

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: rs76704342; hg19: chr5-178700004;