16-77284057-C-T

Position:

chr16-77284057-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_199355.4(ADAMTS18):c.3565G>A(p.Val1189Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00703 in 1,611,594 control chromosomes in the GnomAD database, including 65 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0056 ( 6 hom., cov: 31)

Exomes 𝑓: 0.0072 ( 59 hom. )

Consequence

ADAMTS18
NM_199355.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.422

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=0.009131372).

BP6

Variant 16-77284057-C-T is Benign according to our data. Variant chr16-77284057-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 774925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-77284057-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00557 (847/152040) while in subpopulation SAS AF= 0.00894 (43/4810). AF 95% confidence interval is 0.00706. There are 6 homozygotes in gnomad4. There are 425 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS18	NM_199355.4 link	c.3565G>A	p.Val1189Ile	missense_variant	23/23	ENST00000282849.10	NP_955387.1	Q8TE60-1Q2VYF7Q6ZN25
ADAMTS18	NM_001326358.2 link	c.3049G>A	p.Val1017Ile	missense_variant	23/23		NP_001313287.1
ADAMTS18	XM_047433672.1 link	c.2836G>A	p.Val946Ile	missense_variant	19/19		XP_047289628.1
ADAMTS18	XM_047433673.1 link	c.2329G>A	p.Val777Ile	missense_variant	17/17		XP_047289629.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ADAMTS18	ENST00000282849.10 link	c.3565G>A	p.Val1189Ile	missense_variant	23/23	1	NM_199355.4	ENSP00000282849.5	Q8TE60-1
ADAMTS18	ENST00000562332.1 link	c.94+5207G>A		intron_variant		2		ENSP00000454368.1	H3BMG1
ENSG00000260922	ENST00000561672.1 link	n.74-5219C>T		intron_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00558

AC:

848

AN:

151946

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000721

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00912

Gnomad FIN

AF:

0.0184

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00760

Gnomad OTH

AF:

0.00479

GnomAD3 exomes

AF:

0.00638

AC:

1600

AN:

250750

Hom.:

AF XY:

0.00681

AC XY:

922

AN XY:

135484

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00121

Gnomad ASJ exome

AF:

0.00567

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00983

Gnomad FIN exome

AF:

0.0179

Gnomad NFE exome

AF:

0.00671

Gnomad OTH exome

AF:

0.00540

GnomAD4 exome

AF:

0.00718

AC:

10476

AN:

1459554

Hom.:

Cov.:

AF XY:

0.00719

AC XY:

5225

AN XY:

726298

show subpopulations

Gnomad4 AFR exome

AF:

0.00111

Gnomad4 AMR exome

AF:

0.00116

Gnomad4 ASJ exome

AF:

0.00586

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00975

Gnomad4 FIN exome

AF:

0.0181

Gnomad4 NFE exome

AF:

0.00725

Gnomad4 OTH exome

AF:

0.00609

GnomAD4 genome

AF:

0.00557

AC:

847

AN:

152040

Hom.:

Cov.:

AF XY:

0.00572

AC XY:

425

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.00137

Gnomad4 AMR

AF:

0.000720

Gnomad4 ASJ

AF:

0.00432

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00894

Gnomad4 FIN

AF:

0.0184

Gnomad4 NFE

AF:

0.00760

Gnomad4 OTH

AF:

0.00475

Alfa

AF:

0.00633

Hom.:

Bravo

AF:

0.00386

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.00778

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00663

AC:

ExAC

AF:

0.00623

AC:

756

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.00589

EpiControl

AF:

0.00575

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	ADAMTS18: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.010

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.14

MetaRNN

Benign

0.0091

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.14

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.57

REVEL

Benign

0.0050

Sift

Benign

0.081

Sift4G

Benign

0.19

Polyphen

0.015

Vest4

0.095

MVP

0.33

ClinPred

0.0054

GERP RS

3.0

Varity_R

0.021

gMVP

0.18

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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