rs12935394

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_199355.4(ADAMTS18):c.2836G>T(p.Ala946Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,614,064 control chromosomes in the GnomAD database, including 14,034 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.10 ( 1012 hom., cov: 32)

Exomes 𝑓: 0.13 ( 13022 hom. )

Consequence

ADAMTS18
NM_199355.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.15

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 links:

ENSG00000260922 (HGNC:):

ENSG00000260922 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026280582).

BP6

Variant 16-77295093-C-A is Benign according to our data. Variant chr16-77295093-C-A is described in ClinVar as [Benign]. Clinvar id is 1166617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-77295093-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS18	NM_199355.4 link	c.2836G>T	p.Ala946Ser	missense_variant	19/23	ENST00000282849.10	NP_955387.1	Q8TE60-1Q2VYF7Q6ZN25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS18	ENST00000282849.10 link	c.2836G>T	p.Ala946Ser	missense_variant	19/23	1	NM_199355.4	ENSP00000282849.5		Q8TE60-1
ENSG00000260922	ENST00000648730.1 link	n.118-3797C>A		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.102

AC:

15480

AN:

152102

Hom.:

1012

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0228

Gnomad AMI

AF:

0.140

Gnomad AMR

AF:

0.171

Gnomad ASJ

AF:

0.186

Gnomad EAS

AF:

0.187

Gnomad SAS

AF:

0.117

Gnomad FIN

AF:

0.0782

Gnomad MID

AF:

0.0669

Gnomad NFE

AF:

0.125

Gnomad OTH

AF:

0.120

GnomAD3 exomes

AF:

0.135

AC:

33918

AN:

250998

Hom.:

2718

AF XY:

0.134

AC XY:

18185

AN XY:

135650

show subpopulations

Gnomad AFR exome

AF:

0.0215

Gnomad AMR exome

AF:

0.210

Gnomad ASJ exome

AF:

0.191

Gnomad EAS exome

AF:

0.183

Gnomad SAS exome

AF:

0.132

Gnomad FIN exome

AF:

0.0772

Gnomad NFE exome

AF:

0.128

Gnomad OTH exome

AF:

0.130

GnomAD4 exome

AF:

0.130

AC:

190155

AN:

1461844

Hom.:

13022

Cov.:

AF XY:

0.130

AC XY:

94657

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.0191

Gnomad4 AMR exome

AF:

0.209

Gnomad4 ASJ exome

AF:

0.194

Gnomad4 EAS exome

AF:

0.191

Gnomad4 SAS exome

AF:

0.133

Gnomad4 FIN exome

AF:

0.0819

Gnomad4 NFE exome

AF:

0.129

Gnomad4 OTH exome

AF:

0.132

GnomAD4 genome

AF:

0.102

AC:

15476

AN:

152220

Hom.:

1012

Cov.:

AF XY:

0.102

AC XY:

7615

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.0227

Gnomad4 AMR

AF:

0.171

Gnomad4 ASJ

AF:

0.186

Gnomad4 EAS

AF:

0.188

Gnomad4 SAS

AF:

0.117

Gnomad4 FIN

AF:

0.0782

Gnomad4 NFE

AF:

0.125

Gnomad4 OTH

AF:

0.119

Alfa

AF:

0.125

Hom.:

3157

Bravo

AF:

0.108

TwinsUK

AF:

0.134

AC:

497

ALSPAC

AF:

0.123

AC:

474

ESP6500AA

AF:

0.0216

AC:

ESP6500EA

AF:

0.131

AC:

1125

ExAC

AF:

0.131

AC:

15912

Asia WGS

AF:

0.139

AC:

481

AN:

3478

EpiCase

AF:

0.127

EpiControl

AF:

0.133

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.95

DANN

Benign

0.63

DEOGEN2

Benign

0.0084

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.32

MetaRNN

Benign

0.0026

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.7

PrimateAI

Benign

0.42

PROVEAN

Benign

1.5

REVEL

Benign

0.058

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.049

ClinPred

0.0051

GERP RS

3.3

Varity_R

0.032

gMVP

0.12

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over