rs16945612

Variant names:

• chr16-77395075-T-C
• rs16945612
• NM_199355.4:c.496-27352A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_199355.4(ADAMTS18):​c.496-27352A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 152,160 control chromosomes in the GnomAD database, including 1,608 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.13 (1608 hom., cov: 32)
• Consequence: ADAMTS18 NM_199355.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.883
• Publications: 14 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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• inherited retinal dystrophy

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS18	NM_199355.4	c.496-27352A>G		intron_variant	Intron 3 of 22	ENST00000282849.10	NP_955387.1
ADAMTS18	NM_001326358.2	c.-25-27352A>G		intron_variant	Intron 3 of 22		NP_001313287.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS18	ENST00000282849.10	c.496-27352A>G		intron_variant	Intron 3 of 22	1	NM_199355.4	ENSP00000282849.5

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19617 AN: 152042 Hom.: 1604 Cov.: 32

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0797

Gnomad ASJ AF: 0.0568

Gnomad EAS AF: 0.0364

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.0983

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0999

Gnomad OTH AF: 0.117

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.129 AC: 19656 AN: 152160 Hom.: 1608 Cov.: 32 AF XY: 0.128 AC XY: 9549 AN XY: 74386

African (AFR) AF: 0.223 AC: 9247 AN: 41490

American (AMR) AF: 0.0797 AC: 1220 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0568 AC: 197 AN: 3470

East Asian (EAS) AF: 0.0361 AC: 187 AN: 5182

South Asian (SAS) AF: 0.139 AC: 671 AN: 4812

European-Finnish (FIN) AF: 0.0983 AC: 1040 AN: 10584

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0999 AC: 6797 AN: 68006

Other (OTH) AF: 0.116 AC: 246 AN: 2112

Alfa AF: 0.105 Hom.: 3898

Bravo AF: 0.127

Asia WGS AF: 0.115 AC: 403 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.80
DANN	Benign	0.82
PhyloP100		-0.88
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs16945612; hg19: chr16-77428972;