chr21-45481557-A-G

Variant names:

• chr21-45481557-A-G
• rs3818661
• NM_001379500.1:c.1612-406A>G

Variant summary

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

The NM_001379500.1(COL18A1):​c.1612-406A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.458 in 152,098 control chromosomes in the GnomAD database, including 17,020 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 0.46 (17020 hom., cov: 34)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.372
• Publications: 3 publications found

Genes affected

COL18A1 (HGNC:2195): (collagen type XVIII alpha 1 chain) This gene encodes the alpha chain of type XVIII collagen. This collagen is one of the multiplexins, extracellular matrix proteins that contain multiple triple-helix domains (collagenous domains) interrupted by non-collagenous domains. A long isoform of the protein has an N-terminal domain that is homologous to the extracellular part of frizzled receptors. Proteolytic processing at several endogenous cleavage sites in the C-terminal domain results in production of endostatin, a potent antiangiogenic protein that is able to inhibit angiogenesis and tumor growth. Mutations in this gene are associated with Knobloch syndrome. The main features of this syndrome involve retinal abnormalities, so type XVIII collagen may play an important role in retinal structure and in neural tube closure. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

COL18A1 Gene-Disease associations (from GenCC):

• Knobloch syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Knobloch syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet
• hereditary glaucoma, primary closed-angle

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.633 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379500.1. 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
	COL18A1	NM_001379500.1	MANE Select	c.1612-406A>G		intron	N/A	NP_001366429.1
	COL18A1	NM_130444.3		c.2857-406A>G		intron	N/A	NP_569711.2
	COL18A1	NM_030582.4		c.2152-406A>G		intron	N/A	NP_085059.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.1612-406A>G		intron	N/A	ENSP00000498485.1
	COL18A1	ENST00000355480.10	TSL:1	c.2152-406A>G		intron	N/A	ENSP00000347665.5
	COL18A1	ENST00000359759.8	TSL:5	c.2857-406A>G		intron	N/A	ENSP00000352798.4

Frequencies

GnomAD3 genomes AF: 0.458 AC: 69544 AN: 151980 Hom.: 17001 Cov.: 34

Gnomad AFR AF: 0.639

Gnomad AMI AF: 0.263

Gnomad AMR AF: 0.422

Gnomad ASJ AF: 0.470

Gnomad EAS AF: 0.472

Gnomad SAS AF: 0.390

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.379

Gnomad OTH AF: 0.459

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

GnomAD4 genome AF: 0.458 AC: 69606 AN: 152098 Hom.: 17020 Cov.: 34 AF XY: 0.456 AC XY: 33868 AN XY: 74342

African (AFR) AF: 0.639 AC: 26517 AN: 41466

American (AMR) AF: 0.421 AC: 6430 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.470 AC: 1633 AN: 3472

East Asian (EAS) AF: 0.472 AC: 2444 AN: 5176

South Asian (SAS) AF: 0.390 AC: 1884 AN: 4830

European-Finnish (FIN) AF: 0.338 AC: 3581 AN: 10592

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.379 AC: 25766 AN: 67954

Other (OTH) AF: 0.458 AC: 967 AN: 2112

Alfa AF: 0.417 Hom.: 1740

Bravo AF: 0.474

Asia WGS AF: 0.445 AC: 1551 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.0
DANN	Benign	0.18
PhyloP100		-0.37
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3818661; hg19: chr21-46901471;