16-77284057-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.422

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]

(HGNC:):

ACMG classification

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 GnomAd at 6 AR gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS18	ENST00000282849.10	c.3565G>A	p.Val1189Ile	missense_variant	23/23	1	NM_199355.4	P1
	ENST00000561672.1	n.74-5219C>T		intron_variant, non_coding_transcript_variant		2
ADAMTS18	ENST00000562332.1	c.96+5207G>A		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00558 AC: 848 AN: 151946 Hom.: 6 Cov.: 31

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.: 13 AF XY: 0.00681 AC XY: 922 AN XY: 135484

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.: 59 Cov.: 29 AF XY: 0.00719 AC XY: 5225 AN XY: 726298

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.: 6 Cov.: 31 AF XY: 0.00572 AC XY: 425 AN XY: 74272

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.: 8

Bravo AF: 0.00386

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00663 AC: 57

ExAC AF: 0.00623 AC: 756

Asia WGS AF: 0.00433 AC: 15 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

Submissions by phenotype

not provided Benign:2

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	15
Dann	Benign	0.94
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.14	T
MetaRNN	Benign	0.0091	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.14	N
MutationTaster	Benign	0.62	D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.0050
Sift	Benign	0.081	T
Sift4G	Benign	0.19	T
Polyphen		0.015	B
Vest4		0.095
MVP		0.33
ClinPred		0.0054	T
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

Other links and lift over

dbSNP: rs61749042; hg19: chr16-77317954; COSMIC: COSV51400051;