chr5-179153548-G-A

Variant names:

• chr5-179153548-G-A
• rs61757478
• NM_014244.5:c.1458C>T

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.1458C>T​(p.Tyr486Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00415 in 1,610,818 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0042 (23 hom.)
• Consequence: ADAMTS2 NM_014244.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.79
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 5-179153548-G-A is Benign according to our data. Variant chr5-179153548-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 353121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.79 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0041 (624/152260) while in subpopulation NFE AF = 0.00553 (376/68002). AF 95% confidence interval is 0.00507. There are 4 homozygotes in GnomAd4. There are 331 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.1458C>T	p.Tyr486Tyr	synonymous	Exon 9 of 22	NP_055059.2	O95450-1
	ADAMTS2	NM_021599.4		c.1458C>T	p.Tyr486Tyr	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.1458C>T	p.Tyr486Tyr	synonymous	Exon 9 of 22	ENSP00000251582.7	O95450-1
	ADAMTS2	ENST00000274609.5	TSL:1	c.1458C>T	p.Tyr486Tyr	synonymous	Exon 9 of 11	ENSP00000274609.5	O95450-2
	ADAMTS2	ENST00000957641.1		c.1458C>T	p.Tyr486Tyr	synonymous	Exon 9 of 22	ENSP00000627700.1

Frequencies

GnomAD3 genomes AF: 0.00410 AC: 624 AN: 152142 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0178

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00553

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00418 AC: 1032 AN: 246670 AF XY: 0.00409

Gnomad AFR exome AF: 0.000499

Gnomad AMR exome AF: 0.00105

Gnomad ASJ exome AF: 0.00280

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0183

Gnomad NFE exome AF: 0.00502

Gnomad OTH exome AF: 0.00314

GnomAD4 exome AF: 0.00416 AC: 6066 AN: 1458558 Hom.: 23 Cov.: 32 AF XY: 0.00417 AC XY: 3029 AN XY: 725710

African (AFR) AF: 0.000388 AC: 13 AN: 33474

American (AMR) AF: 0.00101 AC: 45 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00203 AC: 53 AN: 26118

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.000986 AC: 85 AN: 86206

European-Finnish (FIN) AF: 0.0166 AC: 839 AN: 50402

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00431 AC: 4797 AN: 1111844

Other (OTH) AF: 0.00378 AC: 228 AN: 60364

GnomAD4 genome AF: 0.00410 AC: 624 AN: 152260 Hom.: 4 Cov.: 33 AF XY: 0.00445 AC XY: 331 AN XY: 74456

African (AFR) AF: 0.000337 AC: 14 AN: 41548

American (AMR) AF: 0.000980 AC: 15 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4824

European-Finnish (FIN) AF: 0.0178 AC: 189 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00553 AC: 376 AN: 68002

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00502 Hom.: 0

Bravo AF: 0.00253

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00458

EpiControl AF: 0.00380

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Ehlers-Danlos syndrome, dermatosparaxis type (4)
-	-	2	not provided (2)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	5.4
DANN	Benign	0.66
PhyloP100		2.8
Mutation Taster		=100/0	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: rs61757478; hg19: chr5-178580549; COSMIC: COSV51110154;