16-77351621-A-T

Variant names:

• chr16-77351621-A-T
• rs1428837
• NM_199355.4:c.1614+2112T>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.1614+2112T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0533 in 152,328 control chromosomes in the GnomAD database, including 489 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 0.053 (489 hom., cov: 32)
• Consequence: ADAMTS18 NM_199355.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.781
• Publications: 0 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=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS18	NM_199355.4	c.1614+2112T>A		intron_variant	Intron 10 of 22	ENST00000282849.10	NP_955387.1
ADAMTS18	NM_001326358.2	c.1098+2112T>A		intron_variant	Intron 10 of 22		NP_001313287.1
ADAMTS18	XM_047433672.1	c.1098+2112T>A		intron_variant	Intron 7 of 18		XP_047289628.1
ADAMTS18	XM_047433673.1	c.378+2112T>A		intron_variant	Intron 4 of 16		XP_047289629.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS18	ENST00000282849.10	c.1614+2112T>A		intron_variant	Intron 10 of 22	1	NM_199355.4	ENSP00000282849.5

Frequencies

GnomAD3 genomes AF: 0.0532 AC: 8092 AN: 152210 Hom.: 484 Cov.: 32

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0251

Gnomad ASJ AF: 0.0418

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0437

Gnomad FIN AF: 0.00791

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0160

Gnomad OTH AF: 0.0373

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

GnomAD4 genome AF: 0.0533 AC: 8114 AN: 152328 Hom.: 489 Cov.: 32 AF XY: 0.0517 AC XY: 3851 AN XY: 74498

African (AFR) AF: 0.146 AC: 6088 AN: 41558

American (AMR) AF: 0.0251 AC: 384 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0418 AC: 145 AN: 3468

East Asian (EAS) AF: 0.000770 AC: 4 AN: 5192

South Asian (SAS) AF: 0.0439 AC: 212 AN: 4826

European-Finnish (FIN) AF: 0.00791 AC: 84 AN: 10624

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0160 AC: 1091 AN: 68036

Other (OTH) AF: 0.0369 AC: 78 AN: 2112

Alfa AF: 0.0373 Hom.: 34

Bravo AF: 0.0576

Asia WGS AF: 0.0240 AC: 83 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.8
DANN	Benign	0.73
PhyloP100		0.78
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: rs1428837; hg19: chr16-77385518;