NM_007038.5:c.2075T>C

Variant names:

• chr21-26930036-A-G
• rs226794
• NM_007038.5:c.2075T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007038.5(ADAMTS5):​c.2075T>C​(p.Leu692Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.875 in 1,613,948 control chromosomes in the GnomAD database, including 624,427 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L692L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.89 (60287 hom., cov: 32)
  • Exomes 𝑓: 0.87 (564140 hom.)
• Consequence: ADAMTS5 NM_007038.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.69
• Publications: 45 publications found

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]

ENSG00000223563 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.499245E-6).
• BP6: Variant 21-26930036-A-G is Benign according to our data. Variant chr21-26930036-A-G is described in ClinVar as Benign. ClinVar VariationId is 1249546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.955 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007038.5. 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
	ADAMTS5	NM_007038.5	MANE Select	c.2075T>C	p.Leu692Pro	missense	Exon 7 of 8	NP_008969.2	Q9UNA0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS5	ENST00000284987.6	TSL:1 MANE Select	c.2075T>C	p.Leu692Pro	missense	Exon 7 of 8	ENSP00000284987.5	Q9UNA0
	ADAMTS5	ENST00000970346.1		c.1907T>C	p.Leu636Pro	missense	Exon 6 of 7	ENSP00000640405.1
	ADAMTS5	ENST00000652031.1		n.*806T>C		non_coding_transcript_exon	Exon 8 of 9	ENSP00000498989.1	A0A494C1E4

Frequencies

GnomAD3 genomes AF: 0.885 AC: 134632 AN: 152064 Hom.: 60237 Cov.: 32

Gnomad AFR AF: 0.963

Gnomad AMI AF: 0.921

Gnomad AMR AF: 0.804

Gnomad ASJ AF: 0.882

Gnomad EAS AF: 0.487

Gnomad SAS AF: 0.872

Gnomad FIN AF: 0.845

Gnomad MID AF: 0.940

Gnomad NFE AF: 0.894

Gnomad OTH AF: 0.877

GnomAD2 exomes AF: 0.829 AC: 208200 AN: 251044 AF XY: 0.838

Gnomad AFR exome AF: 0.967

Gnomad AMR exome AF: 0.682

Gnomad ASJ exome AF: 0.880

Gnomad EAS exome AF: 0.469

Gnomad FIN exome AF: 0.847

Gnomad NFE exome AF: 0.893

Gnomad OTH exome AF: 0.854

GnomAD4 exome AF: 0.874 AC: 1278040 AN: 1461766 Hom.: 564140 Cov.: 53 AF XY: 0.874 AC XY: 635903 AN XY: 727194

African (AFR) AF: 0.970 AC: 32469 AN: 33474

American (AMR) AF: 0.696 AC: 31105 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.878 AC: 22932 AN: 26132

East Asian (EAS) AF: 0.462 AC: 18356 AN: 39698

South Asian (SAS) AF: 0.866 AC: 74693 AN: 86256

European-Finnish (FIN) AF: 0.844 AC: 45100 AN: 53412

Middle Eastern (MID) AF: 0.894 AC: 5154 AN: 5768

European-Non Finnish (NFE) AF: 0.896 AC: 995973 AN: 1111912

Other (OTH) AF: 0.865 AC: 52258 AN: 60392

GnomAD4 genome AF: 0.885 AC: 134740 AN: 152182 Hom.: 60287 Cov.: 32 AF XY: 0.879 AC XY: 65346 AN XY: 74378

African (AFR) AF: 0.963 AC: 39999 AN: 41554

American (AMR) AF: 0.804 AC: 12295 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.882 AC: 3060 AN: 3468

East Asian (EAS) AF: 0.487 AC: 2509 AN: 5152

South Asian (SAS) AF: 0.872 AC: 4199 AN: 4816

European-Finnish (FIN) AF: 0.845 AC: 8950 AN: 10592

Middle Eastern (MID) AF: 0.939 AC: 276 AN: 294

European-Non Finnish (NFE) AF: 0.894 AC: 60765 AN: 67988

Other (OTH) AF: 0.876 AC: 1849 AN: 2110

Alfa AF: 0.881 Hom.: 269974

Bravo AF: 0.879

TwinsUK AF: 0.900 AC: 3336

ALSPAC AF: 0.900 AC: 3469

ESP6500AA AF: 0.959 AC: 4227

ESP6500EA AF: 0.892 AC: 7670

ExAC AF: 0.840 AC: 101967

Asia WGS AF: 0.737 AC: 2568 AN: 3478

EpiCase AF: 0.894

EpiControl AF: 0.892

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.041
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	17
DANN	Benign	0.61
DEOGEN2	Benign	0.076	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.28	T
MetaRNN	Benign	0.0000025	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.7	N
PhyloP100		7.7
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	9.3	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.074
MPC		0.72
ClinPred		0.016	T
GERP RS		6.0
Varity_R		0.20
gMVP		0.73
Mutation Taster		=93/7	polymorphism (auto)

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: rs226794; hg19: chr21-28302355; COSMIC: COSV53179651;