16-77315305-A-C

Variant names:

• chr16-77315305-A-C
• rs1019800
• NM_199355.4:c.2532+4544T>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.2532+4544T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.339 in 152,114 control chromosomes in the GnomAD database, including 10,186 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 0.34 (10186 hom., cov: 33)
• Consequence: ADAMTS18 NM_199355.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0460
• Publications: 4 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 (EAS) allele frequency at 95% confidence interval = 0.858 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS18	NM_199355.4	c.2532+4544T>G		intron_variant	Intron 16 of 22	ENST00000282849.10	NP_955387.1
ADAMTS18	NM_001326358.2	c.2016+4544T>G		intron_variant	Intron 16 of 22		NP_001313287.1
ADAMTS18	XM_047433672.1	c.2016+4544T>G		intron_variant	Intron 13 of 18		XP_047289628.1
ADAMTS18	XM_047433673.1	c.1296+4544T>G		intron_variant	Intron 10 of 16		XP_047289629.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS18	ENST00000282849.10	c.2532+4544T>G		intron_variant	Intron 16 of 22	1	NM_199355.4	ENSP00000282849.5
ADAMTS18	ENST00000568393.1	n.303+4544T>G		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.339 AC: 51542 AN: 151996 Hom.: 10175 Cov.: 33

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.316

Gnomad AMR AF: 0.479

Gnomad ASJ AF: 0.358

Gnomad EAS AF: 0.878

Gnomad SAS AF: 0.401

Gnomad FIN AF: 0.315

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.350

Gnomad OTH AF: 0.376

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

GnomAD4 genome AF: 0.339 AC: 51570 AN: 152114 Hom.: 10186 Cov.: 33 AF XY: 0.345 AC XY: 25659 AN XY: 74364

African (AFR) AF: 0.199 AC: 8260 AN: 41520

American (AMR) AF: 0.479 AC: 7322 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.358 AC: 1242 AN: 3472

East Asian (EAS) AF: 0.879 AC: 4537 AN: 5162

South Asian (SAS) AF: 0.400 AC: 1927 AN: 4822

European-Finnish (FIN) AF: 0.315 AC: 3336 AN: 10588

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.350 AC: 23752 AN: 67954

Other (OTH) AF: 0.383 AC: 809 AN: 2114

Alfa AF: 0.349 Hom.: 4991

Bravo AF: 0.351

Asia WGS AF: 0.619 AC: 2147 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	4.5
DANN	Benign	0.66
PhyloP100		-0.046
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: rs1019800; hg19: chr16-77349202;