16-77434661-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_199355.4(ADAMTS18):c.35C>G(p.Pro12Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00756 in 1,479,436 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P12T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0062 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0077 ( 38 hom. )

Consequence

ADAMTS18
NM_199355.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.40

Publications

2 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:

ENSG00000260701 (HGNC:):

ENSG00000260701 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=0.0038737953).

BP6

Variant 16-77434661-G-C is Benign according to our data. Variant chr16-77434661-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00623 (948/152124) while in subpopulation NFE AF = 0.00914 (621/67970). AF 95% confidence interval is 0.00854. There are 6 homozygotes in GnomAd4. There are 469 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS18	NM_199355.4	MANE Select	c.35C>G	p.Pro12Arg	missense	Exon 1 of 23	NP_955387.1
	ADAMTS18	NM_001326358.2		c.-486C>G		5_prime_UTR	Exon 1 of 23	NP_001313287.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ADAMTS18	ENST00000282849.10	TSL:1 MANE Select	c.35C>G	p.Pro12Arg	missense	Exon 1 of 23	ENSP00000282849.5
ADAMTS18	ENST00000449265.2	TSL:2	n.35C>G		non_coding_transcript_exon	Exon 1 of 8	ENSP00000392540.2
ENSG00000260701	ENST00000738653.1		n.90G>C		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.00624

AC:

948

AN:

152016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00157

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.0104

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.0152

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00914

Gnomad OTH

AF:

0.00719

GnomAD2 exomes

AF:

0.00629

AC:

550

AN:

87454

AF XY:

0.00650

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00161

Gnomad ASJ exome

AF:

0.0129

Gnomad EAS exome

AF:

0.000214

Gnomad FIN exome

AF:

0.0185

Gnomad NFE exome

AF:

0.00875

Gnomad OTH exome

AF:

0.00735

GnomAD4 exome

AF:

0.00772

AC:

10243

AN:

1327312

Hom.:

Cov.:

AF XY:

0.00772

AC XY:

5054

AN XY:

654734

show subpopulations

African (AFR)

AF:

0.000859

AC:

AN:

26784

American (AMR)

AF:

0.00228

AC:

AN:

28054

Ashkenazi Jewish (ASJ)

AF:

0.0116

AC:

271

AN:

23264

East Asian (EAS)

AF:

0.0000681

AC:

AN:

29370

South Asian (SAS)

AF:

0.00209

AC:

154

AN:

73652

European-Finnish (FIN)

AF:

0.0174

AC:

576

AN:

33084

Middle Eastern (MID)

AF:

0.00169

AC:

AN:

4132

European-Non Finnish (NFE)

AF:

0.00835

AC:

8796

AN:

1053972

Other (OTH)

AF:

0.00636

AC:

350

AN:

55000

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

601

1203

1804

2406

3007

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

334

668

1002

1336

1670

<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:

0.00623

AC:

948

AN:

152124

Hom.:

Cov.:

AF XY:

0.00631

AC XY:

469

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.00156

AC:

AN:

41544

American (AMR)

AF:

0.00262

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.0104

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0152

AC:

160

AN:

10558

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00914

AC:

621

AN:

67970

Other (OTH)

AF:

0.00712

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

100

149

199

249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00657

Hom.:

Bravo

AF:

0.00478

ExAC

AF:

0.00204

AC:

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.0058

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.37

MetaRNN

Benign

0.0039

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

PhyloP100

1.4

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

0.11

REVEL

Benign

0.033

Sift

Benign

1.0

Sift4G

Benign

0.80

Polyphen

0.0

Vest4

0.099

MVP

0.36

ClinPred

0.010

GERP RS

3.1

PromoterAI

0.074

Neutral

(source)

Varity_R

0.026

gMVP

0.17

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over