NM_014244.5:c.1149C>T

Variant names:

• chr5-179154903-G-A
• rs199664723
• NM_014244.5:c.1149C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_014244.5(ADAMTS2):​c.1149C>T​(p.Thr383Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000271 in 1,613,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T383T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: ADAMTS2 NM_014244.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -2.08
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 5-179154903-G-A is Benign according to our data. Variant chr5-179154903-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 469660.
• BP7: Synonymous conserved (PhyloP=-2.08 with no splicing effect.

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.1149C>T	p.Thr383Thr	synonymous	Exon 7 of 22	NP_055059.2
	ADAMTS2	NM_021599.4		c.1149C>T	p.Thr383Thr	synonymous	Exon 7 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.1149C>T	p.Thr383Thr	synonymous	Exon 7 of 22	ENSP00000251582.7
	ADAMTS2	ENST00000274609.5	TSL:1	c.1149C>T	p.Thr383Thr	synonymous	Exon 7 of 11	ENSP00000274609.5
	ADAMTS2	ENST00000957641.1		c.1149C>T	p.Thr383Thr	synonymous	Exon 7 of 22	ENSP00000627700.1

Frequencies

GnomAD3 genomes AF: 0.000190 AC: 29 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000229 AC: 57 AN: 248690 AF XY: 0.000222

Gnomad AFR exome AF: 0.000188

Gnomad AMR exome AF: 0.000175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000819

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000294

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000279 AC: 408 AN: 1461014 Hom.: 0 Cov.: 33 AF XY: 0.000301 AC XY: 219 AN XY: 726758

African (AFR) AF: 0.000119 AC: 4 AN: 33476

American (AMR) AF: 0.000157 AC: 7 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26120

East Asian (EAS) AF: 0.000479 AC: 19 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.000328 AC: 365 AN: 1111856

Other (OTH) AF: 0.000166 AC: 10 AN: 60348

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152358 Hom.: 0 Cov.: 33 AF XY: 0.000201 AC XY: 15 AN XY: 74496

African (AFR) AF: 0.0000962 AC: 4 AN: 41584

American (AMR) AF: 0.0000653 AC: 1 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000345 Hom.: 0

Bravo AF: 0.000162

EpiCase AF: 0.000273

EpiControl AF: 0.000416

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	1.5
DANN	Benign	0.68
PhyloP100		-2.1
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs199664723; hg19: chr5-178581904;