16-77326022-A-T

Position:

chr16-77326022-A-T

Variant summary

Our verdict is Benign. Variant got -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. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

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

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:

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=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 id is 1169694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-77326022-A-T is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
ADAMTS18	NM_199355.4 linkuse as main transcript	c.1876T>A	p.Leu626Ile	missense_variant	13/23	ENST00000282849.10	NP_955387.1	Q8TE60-1Q2VYF7Q6ZN25
ADAMTS18	NM_001326358.2 linkuse as main transcript	c.1360T>A	p.Leu454Ile	missense_variant	13/23		NP_001313287.1
ADAMTS18	XM_047433672.1 linkuse as main transcript	c.1360T>A	p.Leu454Ile	missense_variant	10/19		XP_047289628.1
ADAMTS18	XM_047433673.1 linkuse as main transcript	c.640T>A	p.Leu214Ile	missense_variant	7/17		XP_047289629.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS18	ENST00000282849.10 linkuse as main transcript	c.1876T>A	p.Leu626Ile	missense_variant	13/23	1	NM_199355.4	ENSP00000282849.5		Q8TE60-1

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

GnomAD3 exomes

AF:

0.438

AC:

109971

AN:

250916

Hom.:

27501

AF XY:

0.432

AC XY:

58551

AN XY:

135606

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 SAS exome

AF:

0.403

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

Gnomad4 AFR exome

AF:

0.192

Gnomad4 AMR exome

AF:

0.595

Gnomad4 ASJ exome

AF:

0.381

Gnomad4 EAS exome

AF:

0.890

Gnomad4 SAS exome

AF:

0.410

Gnomad4 FIN exome

AF:

0.365

Gnomad4 NFE exome

AF:

0.379

Gnomad4 OTH exome

AF:

0.405

GnomAD4 genome

AF:

0.357

AC:

54240

AN:

152046

Hom.:

11204

Cov.:

AF XY:

0.363

AC XY:

26968

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.191

Gnomad4 AMR

AF:

0.497

Gnomad4 ASJ

AF:

0.378

Gnomad4 EAS

AF:

0.879

Gnomad4 SAS

AF:

0.400

Gnomad4 FIN

AF:

0.361

Gnomad4 NFE

AF:

0.381

Gnomad4 OTH

AF:

0.404

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

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	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2019	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

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

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

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

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