21-45447673-A-G

Variant names:

• chr21-45447673-A-G
• rs8133622
• NM_001379500.1:c.107-20569A>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.107-20569A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.213 in 152,112 control chromosomes in the GnomAD database, including 3,432 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 0.21 (3432 hom., cov: 32)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.231
• Publications: 6 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

ENSG00000306053 (HGNC:):

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 (EAS) allele frequency at 95% confidence interval = 0.237 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.107-20569A>G		intron	N/A	NP_001366429.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.107-20569A>G		intron	N/A	ENSP00000498485.1
	ENSG00000306053	ENST00000814973.1		n.141-2662A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32464 AN: 151994 Hom.: 3432 Cov.: 32

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.260

Gnomad EAS AF: 0.248

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.230

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

GnomAD4 genome AF: 0.213 AC: 32463 AN: 152112 Hom.: 3432 Cov.: 32 AF XY: 0.214 AC XY: 15908 AN XY: 74360

African (AFR) AF: 0.213 AC: 8848 AN: 41484

American (AMR) AF: 0.226 AC: 3453 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.260 AC: 901 AN: 3470

East Asian (EAS) AF: 0.248 AC: 1285 AN: 5186

South Asian (SAS) AF: 0.240 AC: 1157 AN: 4822

European-Finnish (FIN) AF: 0.179 AC: 1896 AN: 10578

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.210 AC: 14291 AN: 67964

Other (OTH) AF: 0.230 AC: 485 AN: 2110

Alfa AF: 0.212 Hom.: 704

Bravo AF: 0.218

Asia WGS AF: 0.232 AC: 805 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.28
DANN	Benign	0.80
PhyloP100		-0.23
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: rs8133622; hg19: chr21-46867587;