5-179154123-C-T

Variant names:

• chr5-179154123-C-T
• rs41285549
• NM_014244.5:c.1308G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_014244.5(ADAMTS2):​c.1308G>A​(p.Ala436Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,594,590 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A436A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (14 hom.)
• Consequence: ADAMTS2 NM_014244.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.54
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 5-179154123-C-T is Benign according to our data. Variant chr5-179154123-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 353123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.54 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00297 (452/152294) while in subpopulation NFE AF = 0.00402 (273/67986). AF 95% confidence interval is 0.00362. There are 2 homozygotes in GnomAd4. There are 199 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.1308G>A	p.Ala436Ala	synonymous	Exon 8 of 22	NP_055059.2
	ADAMTS2	NM_021599.4		c.1308G>A	p.Ala436Ala	synonymous	Exon 8 of 11	NP_067610.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS2	ENST00000251582.12	TSL:1 MANE Select	c.1308G>A	p.Ala436Ala	synonymous	Exon 8 of 22	ENSP00000251582.7
	ADAMTS2	ENST00000274609.5	TSL:1	c.1308G>A	p.Ala436Ala	synonymous	Exon 8 of 11	ENSP00000274609.5
	ADAMTS2	ENST00000957641.1		c.1308G>A	p.Ala436Ala	synonymous	Exon 8 of 22	ENSP00000627700.1

Frequencies

GnomAD3 genomes AF: 0.00297 AC: 452 AN: 152176 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00299

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00301

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00402

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00257 AC: 545 AN: 212342 AF XY: 0.00251

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00234

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00307

Gnomad NFE exome AF: 0.00422

Gnomad OTH exome AF: 0.00205

GnomAD4 exome AF: 0.00314 AC: 4535 AN: 1442296 Hom.: 14 Cov.: 32 AF XY: 0.00306 AC XY: 2191 AN XY: 716762

African (AFR) AF: 0.00345 AC: 115 AN: 33346

American (AMR) AF: 0.000419 AC: 18 AN: 42984

Ashkenazi Jewish (ASJ) AF: 0.00224 AC: 58 AN: 25876

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39244

South Asian (SAS) AF: 0.000882 AC: 74 AN: 83890

European-Finnish (FIN) AF: 0.00398 AC: 174 AN: 43688

Middle Eastern (MID) AF: 0.000870 AC: 5 AN: 5746

European-Non Finnish (NFE) AF: 0.00356 AC: 3938 AN: 1107636

Other (OTH) AF: 0.00254 AC: 152 AN: 59886

GnomAD4 genome AF: 0.00297 AC: 452 AN: 152294 Hom.: 2 Cov.: 33 AF XY: 0.00267 AC XY: 199 AN XY: 74476

African (AFR) AF: 0.00298 AC: 124 AN: 41566

American (AMR) AF: 0.000457 AC: 7 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.00301 AC: 32 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00402 AC: 273 AN: 67986

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00133 Hom.: 0

Bravo AF: 0.00269

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	9.8
DANN	Benign	0.86
PhyloP100		-1.5
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41285549; hg19: chr5-178581124; COSMIC: COSV51103051;