rs73806887

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_014244.5(ADAMTS2):ā€‹c.3279T>Cā€‹(p.Cys1093Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,613,802 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.0070 ( 12 hom., cov: 32)
Exomes š‘“: 0.00075 ( 14 hom. )

Consequence

ADAMTS2
NM_014244.5 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.208
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.77).
BP6
Variant 5-179114224-A-G is Benign according to our data. Variant chr5-179114224-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 517917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179114224-A-G is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=0.208 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00698 (1063/152298) while in subpopulation AFR AF= 0.0242 (1006/41556). AF 95% confidence interval is 0.023. There are 12 homozygotes in gnomad4. There are 529 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ADAMTS2NM_014244.5 linkuse as main transcriptc.3279T>C p.Cys1093Cys synonymous_variant 22/22 ENST00000251582.12 NP_055059.2 O95450-1
ADAMTS2XM_047417895.1 linkuse as main transcriptc.2784T>C p.Cys928Cys synonymous_variant 21/21 XP_047273851.1
ADAMTS2XM_047417896.1 linkuse as main transcriptc.2397T>C p.Cys799Cys synonymous_variant 20/20 XP_047273852.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ADAMTS2ENST00000251582.12 linkuse as main transcriptc.3279T>C p.Cys1093Cys synonymous_variant 22/221 NM_014244.5 ENSP00000251582.7 O95450-1
ADAMTS2ENST00000522937.1 linkuse as main transcriptn.295T>C non_coding_transcript_exon_variant 2/22

Frequencies

GnomAD3 genomes
AF:
0.00696
AC:
1059
AN:
152180
Hom.:
12
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00268
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00526
GnomAD3 exomes
AF:
0.00192
AC:
482
AN:
251224
Hom.:
6
AF XY:
0.00136
AC XY:
184
AN XY:
135756
show subpopulations
Gnomad AFR exome
AF:
0.0271
Gnomad AMR exome
AF:
0.000955
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.000815
GnomAD4 exome
AF:
0.000752
AC:
1099
AN:
1461504
Hom.:
14
Cov.:
32
AF XY:
0.000637
AC XY:
463
AN XY:
726964
show subpopulations
Gnomad4 AFR exome
AF:
0.0261
Gnomad4 AMR exome
AF:
0.00121
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000928
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000468
Gnomad4 OTH exome
AF:
0.00179
GnomAD4 genome
AF:
0.00698
AC:
1063
AN:
152298
Hom.:
12
Cov.:
32
AF XY:
0.00710
AC XY:
529
AN XY:
74478
show subpopulations
Gnomad4 AFR
AF:
0.0242
Gnomad4 AMR
AF:
0.00268
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00521
Alfa
AF:
0.00381
Hom.:
0
Bravo
AF:
0.00781
Asia WGS
AF:
0.00173
AC:
6
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type Benign:3
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Benign, no assertion criteria providedclinical testingNatera, Inc.Dec 02, 2019- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Ehlers-Danlos syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenNov 29, 2021- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxMar 13, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.77
CADD
Benign
8.7
DANN
Benign
0.51

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs73806887; hg19: chr5-178541225; API