rs775509290

chr5-179345240-G-GGCGGCAGGA

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP3 BP6 BS1 BS2

The NM_014244.5(ADAMTS2):c.88_89insTCCTGCCGC(p.Leu27_Pro29dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0022 in 1,146,494 control chromosomes in the GnomAD database, including 48 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.012 (38 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (10 hom.)
• Consequence: ADAMTS2 NM_014244.5 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 1.05

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 Benign. Variant got -10 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_014244.5
• BP6: Variant 5-179345240-G-GGCGGCAGGA is Benign according to our data. Variant chr5-179345240-G-GGCGGCAGGA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 421230.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.012 (1775/147860) while in subpopulation AFR AF= 0.0409 (1663/40642). AF 95% confidence interval is 0.0393. There are 38 homozygotes in gnomad4. There are 821 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 37 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS2	NM_014244.5	c.88_89insTCCTGCCGC	p.Leu27_Pro29dup	inframe_insertion	1/22	ENST00000251582.12
ADAMTS2	NM_021599.4	c.88_89insTCCTGCCGC	p.Leu27_Pro29dup	inframe_insertion	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.88_89insTCCTGCCGC	p.Leu27_Pro29dup	inframe_insertion	1/22	1	NM_014244.5	P2
ADAMTS2	ENST00000274609.5	c.88_89insTCCTGCCGC	p.Leu27_Pro29dup	inframe_insertion	1/11	1
ADAMTS2	ENST00000518335.3	c.88_89insTCCTGCCGC	p.Leu27_Pro29dup	inframe_insertion	1/21	3		A2
ADAMTS2	ENST00000698889.1	c.88_89insTCCTGCCGC	p.Leu27_Pro29dup	inframe_insertion, NMD_transcript_variant	1/21

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1772 AN: 147752 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.0410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00584

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.0000450

Gnomad OTH AF: 0.0103

GnomAD4 exome AF: 0.000749 AC: 748 AN: 998634 Hom.: 10 Cov.: 30 AF XY: 0.000661 AC XY: 315 AN XY: 476734

Gnomad4 AFR exome AF: 0.0313

Gnomad4 AMR exome AF: 0.00382

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000637

Gnomad4 NFE exome AF: 0.0000241

Gnomad4 OTH exome AF: 0.00245

GnomAD4 genome AF: 0.0120 AC: 1775 AN: 147860 Hom.: 38 Cov.: 32 AF XY: 0.0114 AC XY: 821 AN XY: 72054

Gnomad4 AFR AF: 0.0409

Gnomad4 AMR AF: 0.00583

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000450

Gnomad4 OTH AF: 0.0102

Alfa AF: 0.0119 Hom.: 0

Asia WGS AF: 0.00298 AC: 9 AN: 3036

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 15, 2023	Variant summary: ADAMTS2 c.80_88dupTCCTGCCGC (p.Leu27_Pro29dup) results in an in-frame duplication that is predicted to duplicate 3 amino acids into the encoded protein. The variant allele was found at a frequency of 0.012 in 146532 control chromosomes, predominantly at a frequency of 0.041 within the African or African-American subpopulation in the gnomAD v3.1.2 database, including 36 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 14-fold of the estimated maximal expected allele frequency for a pathogenic variant in ADAMTS2 causing Ehlers-Danlos Syndrome, Type VIIC (Dermatosparaxis) phenotype (0.0029), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.80_88dupTCCTGCCGC in individuals affected with Ehlers-Danlos Syndrome, Type VIIC (Dermatosparaxis) and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign/likely benign (n=3) and as uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 07, 2018	- -

Ehlers-Danlos syndrome, dermatosparaxis type Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 17, 2022

This variant, c.80_88dup, results in the insertion of 3 amino acid(s) of the ADAMTS2 protein (p.Leu27_Pro29dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with ADAMTS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 421230). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Ehlers-Danlos syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 02, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs775509290; hg19: chr5-178772241;