Genetic Variant NM_080722.4:c.1769T>C (chr10-70741007-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_080722.4(ADAMTS14):c.1769T>C(p.Leu590Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.856 in 1,613,930 control chromosomes in the GnomAD database, including 593,328 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.82 ( 51169 hom., cov: 33)

Exomes 𝑓: 0.86 ( 542159 hom. )

Consequence

ADAMTS14
NM_080722.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.911

Publications

34 publications found

Variant links:

Genes affected

ADAMTS14 (HGNC:14899): (ADAM metallopeptidase with thrombospondin type 1 motif 14) This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motif) 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 cleaves amino-terminal propeptides from type I procollagen, a necessary step in the formation of collagen fibers. Mutations in this gene may be associated with osteoarthritis in human patients. [provided by RefSeq, May 2016]

ADAMTS14 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.8301546E-6).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.899 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS14	NM_080722.4 link	c.1769T>C	p.Leu590Pro	missense_variant	Exon 12 of 22	ENST00000373207.2	NP_542453.2	Q8WXS8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS14	ENST00000373207.2 link	c.1769T>C	p.Leu590Pro	missense_variant	Exon 12 of 22	1	NM_080722.4	ENSP00000362303.1		Q8WXS8-1
ADAMTS14	ENST00000373208.5 link	c.1778T>C	p.Leu593Pro	missense_variant	Exon 12 of 22	2		ENSP00000362304.1		Q8WXS8-4

Frequencies

GnomAD3 genomes

AF:

0.816

AC:

124101

AN:

152080

Hom.:

51153

Cov.:

show subpopulations

Gnomad AFR

AF:

0.709

Gnomad AMI

AF:

0.662

Gnomad AMR

AF:

0.752

Gnomad ASJ

AF:

0.878

Gnomad EAS

AF:

0.921

Gnomad SAS

AF:

0.859

Gnomad FIN

AF:

0.937

Gnomad MID

AF:

0.867

Gnomad NFE

AF:

0.865

Gnomad OTH

AF:

0.796

GnomAD2 exomes

AF:

0.838

AC:

210551

AN:

251132

AF XY:

0.846

show subpopulations

Gnomad AFR exome

AF:

0.703

Gnomad AMR exome

AF:

0.696

Gnomad ASJ exome

AF:

0.880

Gnomad EAS exome

AF:

0.919

Gnomad FIN exome

AF:

0.934

Gnomad NFE exome

AF:

0.861

Gnomad OTH exome

AF:

0.845

GnomAD4 exome

AF:

0.860

AC:

1257062

AN:

1461732

Hom.:

542159

Cov.:

AF XY:

0.861

AC XY:

626176

AN XY:

727166

show subpopulations

African (AFR)

AF:

0.705

AC:

23590

AN:

33476

American (AMR)

AF:

0.703

AC:

31451

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.878

AC:

22953

AN:

26134

East Asian (EAS)

AF:

0.922

AC:

36583

AN:

39698

South Asian (SAS)

AF:

0.858

AC:

73981

AN:

86256

European-Finnish (FIN)

AF:

0.926

AC:

49389

AN:

53348

Middle Eastern (MID)

AF:

0.831

AC:

4791

AN:

5768

European-Non Finnish (NFE)

AF:

0.866

AC:

962700

AN:

1111940

Other (OTH)

AF:

0.855

AC:

51624

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

10090

20179

30269

40358

50448

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21234

42468

63702

84936

106170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.816

AC:

124164

AN:

152198

Hom.:

51169

Cov.:

AF XY:

0.819

AC XY:

60946

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.709

AC:

29396

AN:

41480

American (AMR)

AF:

0.751

AC:

11480

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.878

AC:

3049

AN:

3472

East Asian (EAS)

AF:

0.921

AC:

4768

AN:

5176

South Asian (SAS)

AF:

0.859

AC:

4146

AN:

4826

European-Finnish (FIN)

AF:

0.937

AC:

9959

AN:

10624

Middle Eastern (MID)

AF:

0.861

AC:

253

AN:

294

European-Non Finnish (NFE)

AF:

0.865

AC:

58824

AN:

68010

Other (OTH)

AF:

0.798

AC:

1687

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1143

2286

3430

4573

5716

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

880

1760

2640

3520

4400

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.841

Hom.:

151254

Bravo

AF:

0.794

TwinsUK

AF:

0.859

AC:

3184

ALSPAC

AF:

0.871

AC:

3356

ESP6500AA

AF:

0.709

AC:

3122

ESP6500EA

AF:

0.859

AC:

7391

ExAC

AF:

0.840

AC:

101944

Asia WGS

AF:

0.864

AC:

3000

AN:

3478

EpiCase

AF:

0.853

EpiControl

AF:

0.849

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.042

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.81

CADD

Benign

9.6

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.011

.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.078

LIST_S2

Benign

0.23

T;T

MetaRNN

Benign

0.0000018

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.8

.;N

PhyloP100

0.91

PrimateAI

Benign

0.24

PROVEAN

Benign

2.0

N;N

REVEL

Benign

0.051

Sift

Benign

0.41

T;T

Sift4G

Benign

0.24

T;T

Polyphen

0.0

.;B

Vest4

0.038

MPC

0.27

ClinPred

0.0014

GERP RS

-2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.074

gMVP

0.32

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over