16-77284057-C-T

Variant names:

• chr16-77284057-C-T
• rs61749042
• NM_199355.4:c.3565G>A

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1189G) has been classified as Uncertain significance.

• 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
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• microcornea-myopic chorioretinal atrophy

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P
• inherited retinal dystrophy

  Inheritance: AR Classification: LIMITED Submitted by: Franklin by Genoox

ENSG00000260922 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 774925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199355.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS18	NM_199355.4	MANE Select	c.3565G>A	p.Val1189Ile	missense	Exon 23 of 23	NP_955387.1	Q8TE60-1
	ADAMTS18	NM_001326358.2		c.3049G>A	p.Val1017Ile	missense	Exon 23 of 23	NP_001313287.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS18	ENST00000282849.10	TSL:1 MANE Select	c.3565G>A	p.Val1189Ile	missense	Exon 23 of 23	ENSP00000282849.5	Q8TE60-1
	ADAMTS18	ENST00000562332.1	TSL:2	c.94+5207G>A		intron	N/A	ENSP00000454368.1	H3BMG1
	ENSG00000260922	ENST00000561672.1	TSL:2	n.74-5219C>T		intron	N/A

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

GnomAD2 exomes AF: 0.00638 AC: 1600 AN: 250750 AF XY: 0.00681

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 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

African (AFR) AF: 0.00111 AC: 37 AN: 33422

American (AMR) AF: 0.00116 AC: 52 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00586 AC: 153 AN: 26126

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39674

South Asian (SAS) AF: 0.00975 AC: 841 AN: 86222

European-Finnish (FIN) AF: 0.0181 AC: 968 AN: 53402

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5764

European-Non Finnish (NFE) AF: 0.00725 AC: 8045 AN: 1109922

Other (OTH) AF: 0.00609 AC: 367 AN: 60306

GnomAD4 genome AF: 0.00557 AC: 847 AN: 152040 Hom.: 6 Cov.: 31 AF XY: 0.00572 AC XY: 425 AN XY: 74272

African (AFR) AF: 0.00137 AC: 57 AN: 41482

American (AMR) AF: 0.000720 AC: 11 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00894 AC: 43 AN: 4810

European-Finnish (FIN) AF: 0.0184 AC: 194 AN: 10520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00760 AC: 517 AN: 68008

Other (OTH) AF: 0.00475 AC: 10 AN: 2106

Alfa AF: 0.00616 Hom.: 10

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.42
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
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

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