chr21-45412007-G-A

Variant names:

• chr21-45412007-G-A
• rs1004133
• NM_001379500.1:c.106+6534G>A

Variant summary

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

The NM_001379500.1(COL18A1):​c.106+6534G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.515 in 151,950 control chromosomes in the GnomAD database, including 21,987 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 0.52 (21987 hom., cov: 31)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.25
• Publications: 1 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• 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=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.618 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	NM_001379500.1	MANE Select	c.106+6534G>A		intron	N/A	NP_001366429.1	P39060-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.106+6534G>A		intron	N/A	ENSP00000498485.1	P39060-2
	COL18A1	ENST00000859062.1		c.106+6534G>A		intron	N/A	ENSP00000529121.1
	COL18A1	ENST00000930602.1		c.106+6534G>A		intron	N/A	ENSP00000600661.1

Frequencies

GnomAD3 genomes AF: 0.516 AC: 78301 AN: 151832 Hom.: 21995 Cov.: 31

Gnomad AFR AF: 0.316

Gnomad AMI AF: 0.643

Gnomad AMR AF: 0.502

Gnomad ASJ AF: 0.710

Gnomad EAS AF: 0.242

Gnomad SAS AF: 0.583

Gnomad FIN AF: 0.649

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.623

Gnomad OTH AF: 0.540

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

GnomAD4 genome AF: 0.515 AC: 78308 AN: 151950 Hom.: 21987 Cov.: 31 AF XY: 0.516 AC XY: 38354 AN XY: 74274

African (AFR) AF: 0.315 AC: 13052 AN: 41388

American (AMR) AF: 0.501 AC: 7662 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.710 AC: 2462 AN: 3468

East Asian (EAS) AF: 0.242 AC: 1249 AN: 5154

South Asian (SAS) AF: 0.584 AC: 2811 AN: 4816

European-Finnish (FIN) AF: 0.649 AC: 6857 AN: 10562

Middle Eastern (MID) AF: 0.622 AC: 183 AN: 294

European-Non Finnish (NFE) AF: 0.623 AC: 42314 AN: 67954

Other (OTH) AF: 0.536 AC: 1132 AN: 2110

Alfa AF: 0.580 Hom.: 38718

Bravo AF: 0.491

Asia WGS AF: 0.441 AC: 1531 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.3
DANN	Benign	0.76
PhyloP100		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1004133; hg19: chr21-46831922;