16-77420691-G-T

Variant names:

• chr16-77420691-G-T
• rs768503
• NM_199355.4:c.495+10604C>A

Variant summary

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

The NM_199355.4(ADAMTS18):​c.495+10604C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 152,130 control chromosomes in the GnomAD database, including 1,336 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 (1336 hom., cov: 33)
• Consequence: ADAMTS18 NM_199355.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.230
• Publications: 3 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS18	NM_199355.4	MANE Select	c.495+10604C>A		intron	N/A	NP_955387.1
	ADAMTS18	NM_001326358.2		c.-26+10604C>A		intron	N/A	NP_001313287.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS18	ENST00000282849.10	TSL:1 MANE Select	c.495+10604C>A		intron	N/A	ENSP00000282849.5
	ADAMTS18	ENST00000562345.1	TSL:5	c.291+10604C>A		intron	N/A	ENSP00000457395.1
	ADAMTS18	ENST00000449265.2	TSL:2	n.495+10604C>A		intron	N/A	ENSP00000392540.2

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19723 AN: 152012 Hom.: 1335 Cov.: 33

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.0465

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.193

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.117

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

GnomAD4 genome AF: 0.130 AC: 19731 AN: 152130 Hom.: 1336 Cov.: 33 AF XY: 0.133 AC XY: 9901 AN XY: 74370

African (AFR) AF: 0.134 AC: 5551 AN: 41498

American (AMR) AF: 0.117 AC: 1782 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 407 AN: 3468

East Asian (EAS) AF: 0.0464 AC: 240 AN: 5176

South Asian (SAS) AF: 0.125 AC: 604 AN: 4822

European-Finnish (FIN) AF: 0.193 AC: 2044 AN: 10566

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.128 AC: 8689 AN: 67992

Other (OTH) AF: 0.115 AC: 243 AN: 2112

Alfa AF: 0.126 Hom.: 2389

Bravo AF: 0.122

Asia WGS AF: 0.0750 AC: 261 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.58
DANN	Benign	0.41
PhyloP100		-0.23
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: rs768503; hg19: chr16-77454588;