chr21-45433064-C-G

Variant names:

• chr21-45433064-C-G
• rs8129539
• NM_001379500.1:c.106+27591C>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.106+27591C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 152,160 control chromosomes in the GnomAD database, including 3,271 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 0.18 (3271 hom., cov: 33)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.712
• 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: 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.331 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.106+27591C>G		intron_variant	Intron 2 of 41	ENST00000651438.1	NP_001366429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.106+27591C>G		intron_variant	Intron 2 of 41		NM_001379500.1	ENSP00000498485.1

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26962 AN: 152044 Hom.: 3267 Cov.: 33

Gnomad AFR AF: 0.336

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.239

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.170

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

GnomAD4 genome AF: 0.177 AC: 26995 AN: 152160 Hom.: 3271 Cov.: 33 AF XY: 0.177 AC XY: 13199 AN XY: 74374

African (AFR) AF: 0.336 AC: 13924 AN: 41458

American (AMR) AF: 0.129 AC: 1971 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 572 AN: 3468

East Asian (EAS) AF: 0.239 AC: 1236 AN: 5178

South Asian (SAS) AF: 0.106 AC: 512 AN: 4824

European-Finnish (FIN) AF: 0.123 AC: 1304 AN: 10596

Middle Eastern (MID) AF: 0.140 AC: 41 AN: 292

European-Non Finnish (NFE) AF: 0.102 AC: 6968 AN: 68014

Other (OTH) AF: 0.168 AC: 356 AN: 2116

Alfa AF: 0.0448 Hom.: 42

Bravo AF: 0.187

Asia WGS AF: 0.173 AC: 604 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.0
DANN	Benign	0.45
PhyloP100		0.71
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: rs8129539; hg19: chr21-46852978;