rs9930984

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_199355.4(ADAMTS18):c.2305C>A(p.Leu769Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.437 in 1,613,458 control chromosomes in the GnomAD database, including 166,153 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.52 ( 22941 hom., cov: 32)

Exomes 𝑓: 0.43 ( 143212 hom. )

Consequence

ADAMTS18
NM_199355.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.53

Publications

33 publications found

Variant links:

Genes affected

ADAMTS18 (HGNC:17110): (ADAM metallopeptidase with thrombospondin type 1 motif 18) This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. ADAMTS family members 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 protein, which may regulate hemostatic balance and function as a tumor suppressor. Mutations in this gene may be associated with microcornea, myopic chorioretinal atrophy, and telecanthus (MMCAT) and cone-rod dystrophy in human patients. [provided by RefSeq, May 2016]

ADAMTS18 Gene-Disease associations (from GenCC):

microcornea-myopic chorioretinal atrophy
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P
inherited retinal dystrophy
Inheritance: AR Classification: LIMITED Submitted by: Franklin by Genoox

ADAMTS18 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=2.776122E-6).

BP6

Variant 16-77320076-G-T is Benign according to our data. Variant chr16-77320076-G-T is described in ClinVar as Benign. ClinVar VariationId is 1168652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.857 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199355.4. 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
	ADAMTS18	NM_199355.4	MANE Select	c.2305C>A	p.Leu769Ile	missense	Exon 16 of 23	NP_955387.1	Q8TE60-1
	ADAMTS18	NM_001326358.2		c.1789C>A	p.Leu597Ile	missense	Exon 16 of 23	NP_001313287.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS18	ENST00000282849.10	TSL:1 MANE Select	c.2305C>A	p.Leu769Ile	missense	Exon 16 of 23	ENSP00000282849.5	Q8TE60-1
	ADAMTS18	ENST00000568393.1	TSL:3	n.76C>A		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes

AF:

0.523

AC:

79325

AN:

151788

Hom.:

22906

Cov.:

show subpopulations

Gnomad AFR

AF:

0.741

Gnomad AMI

AF:

0.302

Gnomad AMR

AF:

0.560

Gnomad ASJ

AF:

0.388

Gnomad EAS

AF:

0.878

Gnomad SAS

AF:

0.485

Gnomad FIN

AF:

0.341

Gnomad MID

AF:

0.396

Gnomad NFE

AF:

0.396

Gnomad OTH

AF:

0.501

GnomAD2 exomes

AF:

0.497

AC:

123742

AN:

249074

AF XY:

0.483

show subpopulations

Gnomad AFR exome

AF:

0.753

Gnomad AMR exome

AF:

0.641

Gnomad ASJ exome

AF:

0.388

Gnomad EAS exome

AF:

0.884

Gnomad FIN exome

AF:

0.347

Gnomad NFE exome

AF:

0.393

Gnomad OTH exome

AF:

0.458

GnomAD4 exome

AF:

0.428

AC:

626210

AN:

1461550

Hom.:

143212

Cov.:

AF XY:

0.428

AC XY:

311165

AN XY:

727082

show subpopulations

African (AFR)

AF:

0.755

AC:

25269

AN:

33470

American (AMR)

AF:

0.631

AC:

28201

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.388

AC:

10148

AN:

26134

East Asian (EAS)

AF:

0.890

AC:

35322

AN:

39700

South Asian (SAS)

AF:

0.494

AC:

42566

AN:

86240

European-Finnish (FIN)

AF:

0.347

AC:

18536

AN:

53402

Middle Eastern (MID)

AF:

0.420

AC:

2421

AN:

5766

European-Non Finnish (NFE)

AF:

0.392

AC:

436332

AN:

1111738

Other (OTH)

AF:

0.454

AC:

27415

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

20493

40985

61478

81970

102463

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13922

27844

41766

55688

69610

<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:

0.523

AC:

79408

AN:

151908

Hom.:

22941

Cov.:

AF XY:

0.523

AC XY:

38838

AN XY:

74208

show subpopulations

African (AFR)

AF:

0.741

AC:

30702

AN:

41450

American (AMR)

AF:

0.560

AC:

8552

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.388

AC:

1346

AN:

3468

East Asian (EAS)

AF:

0.878

AC:

4506

AN:

5132

South Asian (SAS)

AF:

0.485

AC:

2328

AN:

4800

European-Finnish (FIN)

AF:

0.341

AC:

3594

AN:

10546

Middle Eastern (MID)

AF:

0.415

AC:

122

AN:

294

European-Non Finnish (NFE)

AF:

0.396

AC:

26915

AN:

67936

Other (OTH)

AF:

0.507

AC:

1069

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1713

3427

5140

6854

8567

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

676

1352

2028

2704

3380

<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:

0.449

Hom.:

55696

Bravo

AF:

0.551

TwinsUK

AF:

0.401

AC:

1488

ALSPAC

AF:

0.390

AC:

1504

ESP6500AA

AF:

0.748

AC:

3290

ESP6500EA

AF:

0.395

AC:

3395

ExAC

AF:

0.496

AC:

60203

Asia WGS

AF:

0.690

AC:

2395

AN:

3478

EpiCase

AF:

0.388

EpiControl

AF:

0.393

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

CADD

Benign

9.9

(source)

DANN

Benign

0.47

DEOGEN2

Benign

0.014

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.074

LIST_S2

Benign

0.14

MetaRNN

Benign

0.0000028

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.045

PhyloP100

2.5

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.040

REVEL

Benign

0.11

Sift

Benign

0.48

Sift4G

Benign

0.47

Polyphen

0.0

Vest4

0.042

ClinPred

0.0051

GERP RS

2.1

Varity_R

0.075

gMVP

0.33

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over