16-77326022-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.22

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]

ACMG classification

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	UniProt
ADAMTS18	NM_199355.4	c.1876T>A	p.Leu626Ile	missense_variant	13/23	ENST00000282849.10
ADAMTS18	NM_001326358.2	c.1360T>A	p.Leu454Ile	missense_variant	13/23
ADAMTS18	XM_047433672.1	c.1360T>A	p.Leu454Ile	missense_variant	10/19
ADAMTS18	XM_047433673.1	c.640T>A	p.Leu214Ile	missense_variant	7/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS18	ENST00000282849.10	c.1876T>A	p.Leu626Ile	missense_variant	13/23	1	NM_199355.4	P1

Frequencies

GnomAD3 genomes AF: 0.357 AC: 54221 AN: 151928 Hom.: 11192 Cov.: 32

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

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.: 40 AF XY: 0.397 AC XY: 288433 AN XY: 726764

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.: 32 AF XY: 0.363 AC XY: 26968 AN XY: 74312

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.071
FATHMM_MKL	Benign	0.32	N
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0000020	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.055	T
Polyphen		0.0070	B
Vest4		0.055
ClinPred		0.079	T
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

Other links and lift over

dbSNP: rs11640912; hg19: chr16-77359919; COSMIC: COSV51420443; COSMIC: COSV51420443;