16-77326022-A-T

Variant names:

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.1876T>A(p.Leu626Ile) variant causes a missense change. The variant allele was found at a frequency of 0.394 in 1,612,920 control chromosomes in the GnomAD database, including 134,471 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 (★★).

Frequency

Genomes: 𝑓 0.36 ( 11204 hom., cov: 32)

Exomes 𝑓: 0.40 ( 123267 hom. )

Consequence

ADAMTS18
NM_199355.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.22

Publications

28 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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), 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=2.0353666E-6).

BP6

Variant 16-77326022-A-T is Benign according to our data. Variant chr16-77326022-A-T is described in ClinVar as Benign. ClinVar VariationId is 1169694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.858 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ADAMTS18	NM_199355.4 link	c.1876T>A	p.Leu626Ile	missense_variant	Exon 13 of 23	ENST00000282849.10	NP_955387.1
ADAMTS18	NM_001326358.2 link	c.1360T>A	p.Leu454Ile	missense_variant	Exon 13 of 23		NP_001313287.1
ADAMTS18	XM_047433672.1 link	c.1360T>A	p.Leu454Ile	missense_variant	Exon 10 of 19		XP_047289628.1
ADAMTS18	XM_047433673.1 link	c.640T>A	p.Leu214Ile	missense_variant	Exon 7 of 17		XP_047289629.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS18	ENST00000282849.10 link	c.1876T>A	p.Leu626Ile	missense_variant	Exon 13 of 23	1	NM_199355.4	ENSP00000282849.5

Frequencies

GnomAD3 genomes

AF:

0.357

AC:

54221

AN:

151928

Hom.:

11192

Cov.:

show subpopulations

Gnomad AFR

AF:

0.191

Gnomad AMI

AF:

0.319

Gnomad AMR

AF:

0.497

Gnomad ASJ

AF:

0.378

Gnomad EAS

AF:

0.879

Gnomad SAS

AF:

0.401

Gnomad FIN

AF:

0.361

Gnomad MID

AF:

0.351

Gnomad NFE

AF:

0.381

Gnomad OTH

AF:

0.396

GnomAD2 exomes

AF:

0.438

AC:

109971

AN:

250916

AF XY:

0.432

show subpopulations

Gnomad AFR exome

AF:

0.192

Gnomad AMR exome

AF:

0.608

Gnomad ASJ exome

AF:

0.380

Gnomad EAS exome

AF:

0.885

Gnomad FIN exome

AF:

0.367

Gnomad NFE exome

AF:

0.379

Gnomad OTH exome

AF:

0.425

GnomAD4 exome

AF:

0.397

AC:

580670

AN:

1460874

Hom.:

123267

Cov.:

AF XY:

0.397

AC XY:

288433

AN XY:

726764

show subpopulations

African (AFR)

AF:

0.192

AC:

6409

AN:

33462

American (AMR)

AF:

0.595

AC:

26573

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.381

AC:

9963

AN:

26126

East Asian (EAS)

AF:

0.890

AC:

35307

AN:

39668

South Asian (SAS)

AF:

0.410

AC:

35340

AN:

86230

European-Finnish (FIN)

AF:

0.365

AC:

19505

AN:

53400

Middle Eastern (MID)

AF:

0.375

AC:

2165

AN:

5766

European-Non Finnish (NFE)

AF:

0.379

AC:

420968

AN:

1111172

Other (OTH)

AF:

0.405

AC:

24440

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

17488

34976

52465

69953

87441

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13356

26712

40068

53424

66780

<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:

0.357

AC:

54240

AN:

152046

Hom.:

11204

Cov.:

AF XY:

0.363

AC XY:

26968

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.191

AC:

7919

AN:

41512

American (AMR)

AF:

0.497

AC:

7585

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.378

AC:

1311

AN:

3468

East Asian (EAS)

AF:

0.879

AC:

4536

AN:

5160

South Asian (SAS)

AF:

0.400

AC:

1928

AN:

4814

European-Finnish (FIN)

AF:

0.361

AC:

3807

AN:

10560

Middle Eastern (MID)

AF:

0.364

AC:

107

AN:

294

European-Non Finnish (NFE)

AF:

0.381

AC:

25903

AN:

67942

Other (OTH)

AF:

0.404

AC:

854

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1692

3384

5075

6767

8459

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

528

1056

1584

2112

2640

<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:

0.391

Hom.:

9383

Bravo

AF:

0.365

TwinsUK

AF:

0.382

AC:

1417

ALSPAC

AF:

0.376

AC:

1449

ESP6500AA

AF:

0.206

AC:

905

ESP6500EA

AF:

0.377

AC:

3239

ExAC

AF:

0.425

AC:

51644

Asia WGS

AF:

0.622

AC:

2158

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 12, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.014

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.071

FATHMM_MKL

Benign

0.32

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.0000020

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

PhyloP100

4.2

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.82

REVEL

Benign

0.12

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.055

Polyphen

0.0070

Vest4

0.055

ClinPred

0.079

GERP RS

4.8

Varity_R

0.49

gMVP

0.35

Mutation Taster

=99/1

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over