chr21-26932893-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_007038.5(ADAMTS5):​c.1841G>A​(p.Arg614His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,613,118 control chromosomes in the GnomAD database, including 18,030 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.12 ( 1266 hom., cov: 32)
Exomes 𝑓: 0.15 ( 16764 hom. )

Consequence

ADAMTS5
NM_007038.5 missense

Scores

4
6
8

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 7.57
Variant links:
Genes affected
ADAMTS5 (HGNC:221): (ADAM metallopeptidase with thrombospondin type 1 motif 5) 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 enzyme. This enzyme contains two C-terminal TS motifs and functions as an aggrecanase that cleaves aggrecan, a major proteoglycan of cartilage, and may mediate cartilage destruction in osteoarthritis. [provided by RefSeq, Feb 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0020451844).
BP6
Variant 21-26932893-C-T is Benign according to our data. Variant chr21-26932893-C-T is described in ClinVar as [Benign]. Clinvar id is 1181193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.15 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ADAMTS5NM_007038.5 linkuse as main transcriptc.1841G>A p.Arg614His missense_variant 5/8 ENST00000284987.6
ADAMTS5XM_047440680.1 linkuse as main transcriptc.1673G>A p.Arg558His missense_variant 4/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ADAMTS5ENST00000284987.6 linkuse as main transcriptc.1841G>A p.Arg614His missense_variant 5/81 NM_007038.5 P1
ENST00000426771.1 linkuse as main transcriptn.235-6723C>T intron_variant, non_coding_transcript_variant 3
ADAMTS5ENST00000652031.1 linkuse as main transcriptc.*572G>A 3_prime_UTR_variant, NMD_transcript_variant 6/9

Frequencies

GnomAD3 genomes
AF:
0.124
AC:
18778
AN:
151978
Hom.:
1268
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0686
Gnomad AMI
AF:
0.329
Gnomad AMR
AF:
0.125
Gnomad ASJ
AF:
0.140
Gnomad EAS
AF:
0.114
Gnomad SAS
AF:
0.0779
Gnomad FIN
AF:
0.144
Gnomad MID
AF:
0.187
Gnomad NFE
AF:
0.152
Gnomad OTH
AF:
0.162
GnomAD3 exomes
AF:
0.125
AC:
31162
AN:
250042
Hom.:
2139
AF XY:
0.126
AC XY:
16990
AN XY:
135096
show subpopulations
Gnomad AFR exome
AF:
0.0638
Gnomad AMR exome
AF:
0.0824
Gnomad ASJ exome
AF:
0.145
Gnomad EAS exome
AF:
0.0869
Gnomad SAS exome
AF:
0.0828
Gnomad FIN exome
AF:
0.150
Gnomad NFE exome
AF:
0.156
Gnomad OTH exome
AF:
0.138
GnomAD4 exome
AF:
0.147
AC:
214833
AN:
1461022
Hom.:
16764
Cov.:
32
AF XY:
0.146
AC XY:
105755
AN XY:
726780
show subpopulations
Gnomad4 AFR exome
AF:
0.0608
Gnomad4 AMR exome
AF:
0.0880
Gnomad4 ASJ exome
AF:
0.144
Gnomad4 EAS exome
AF:
0.130
Gnomad4 SAS exome
AF:
0.0804
Gnomad4 FIN exome
AF:
0.146
Gnomad4 NFE exome
AF:
0.158
Gnomad4 OTH exome
AF:
0.139
GnomAD4 genome
AF:
0.123
AC:
18766
AN:
152096
Hom.:
1266
Cov.:
32
AF XY:
0.122
AC XY:
9079
AN XY:
74342
show subpopulations
Gnomad4 AFR
AF:
0.0684
Gnomad4 AMR
AF:
0.125
Gnomad4 ASJ
AF:
0.140
Gnomad4 EAS
AF:
0.114
Gnomad4 SAS
AF:
0.0773
Gnomad4 FIN
AF:
0.144
Gnomad4 NFE
AF:
0.152
Gnomad4 OTH
AF:
0.160
Alfa
AF:
0.149
Hom.:
4481
Bravo
AF:
0.123
TwinsUK
AF:
0.163
AC:
603
ALSPAC
AF:
0.157
AC:
607
ESP6500AA
AF:
0.0724
AC:
319
ESP6500EA
AF:
0.160
AC:
1372
ExAC
AF:
0.125
AC:
15208
Asia WGS
AF:
0.0870
AC:
302
AN:
3478
EpiCase
AF:
0.158
EpiControl
AF:
0.163

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxJul 15, 2020This variant is associated with the following publications: (PMID: 22961118) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.21
BayesDel_addAF
Benign
-0.40
T
BayesDel_noAF
Benign
-0.21
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.34
T
Eigen
Pathogenic
0.95
Eigen_PC
Pathogenic
0.91
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D
MetaRNN
Benign
0.0020
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.6
M
MutationTaster
Benign
1.5e-8
P
PrimateAI
Uncertain
0.64
T
PROVEAN
Uncertain
-3.7
D
REVEL
Uncertain
0.40
Sift
Uncertain
0.0010
D
Sift4G
Benign
0.071
T
Polyphen
1.0
D
Vest4
0.27
MPC
1.5
ClinPred
0.025
T
GERP RS
6.0
Varity_R
0.85
gMVP
0.62

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs2830585; hg19: chr21-28305212; COSMIC: COSV53175235; API