rs147438064

Variant names:

• chr5-179153518-G-A
• rs147438064
• NM_014244.5:c.1488C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-179153518-G-A
• chr5-179153518-G-C
• chr5-179153518-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_014244.5(ADAMTS2):​c.1488C>T​(p.Phe496Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00273 in 1,610,534 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (9 hom.)
• Consequence: ADAMTS2 NM_014244.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.545
• 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), G2P, Orphanet, Illumina, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 5-179153518-G-A is Benign according to our data. Variant chr5-179153518-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 381211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.545 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00283 (4127/1458276) while in subpopulation NFE AF = 0.00339 (3766/1111870). AF 95% confidence interval is 0.0033. There are 9 homozygotes in GnomAdExome4. There are 2048 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 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.1488C>T	p.Phe496Phe	synonymous	Exon 9 of 22	NP_055059.2	O95450-1
	ADAMTS2	NM_021599.4		c.1488C>T	p.Phe496Phe	synonymous	Exon 9 of 11	NP_067610.1	O95450-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS2	ENST00000251582.12	TSL:1 MANE Select	c.1488C>T	p.Phe496Phe	synonymous	Exon 9 of 22	ENSP00000251582.7	O95450-1
	ADAMTS2	ENST00000274609.5	TSL:1	c.1488C>T	p.Phe496Phe	synonymous	Exon 9 of 11	ENSP00000274609.5	O95450-2
	ADAMTS2	ENST00000957641.1		c.1488C>T	p.Phe496Phe	synonymous	Exon 9 of 22	ENSP00000627700.1

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 269 AN: 152140 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00367

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00300

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00208 AC: 513 AN: 247222 AF XY: 0.00192

Gnomad AFR exome AF: 0.000560

Gnomad AMR exome AF: 0.000464

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00410

Gnomad NFE exome AF: 0.00351

Gnomad OTH exome AF: 0.00247

GnomAD4 exome AF: 0.00283 AC: 4127 AN: 1458276 Hom.: 9 Cov.: 32 AF XY: 0.00282 AC XY: 2048 AN XY: 725670

African (AFR) AF: 0.000508 AC: 17 AN: 33476

American (AMR) AF: 0.000425 AC: 19 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86242

European-Finnish (FIN) AF: 0.00450 AC: 225 AN: 50042

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00339 AC: 3766 AN: 1111870

Other (OTH) AF: 0.00162 AC: 98 AN: 60364

GnomAD4 genome AF: 0.00177 AC: 269 AN: 152258 Hom.: 0 Cov.: 33 AF XY: 0.00154 AC XY: 115 AN XY: 74454

African (AFR) AF: 0.000337 AC: 14 AN: 41554

American (AMR) AF: 0.000523 AC: 8 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00367 AC: 39 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00300 AC: 204 AN: 68006

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00211 Hom.: 0

Bravo AF: 0.00155

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00207

EpiControl AF: 0.00267

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Ehlers-Danlos syndrome, dermatosparaxis type (3)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	7.8
DANN	Benign	0.74
PhyloP100		-0.55
Mutation Taster		=91/9	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: rs147438064; hg19: chr5-178580519; COSMIC: COSV51095161;