rs8126757

Positions:

• chr21-45428367-A-G
• chr21-45428367-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001379500.1(COL18A1):​c.106+22894A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 152,104 control chromosomes in the GnomAD database, including 8,117 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 0.29 (8117 hom., cov: 33)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.265

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL18A1	NM_001379500.1	c.106+22894A>G		intron_variant		ENST00000651438.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL18A1	ENST00000651438.1	c.106+22894A>G		intron_variant			NM_001379500.1

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43713 AN: 151986 Hom.: 8083 Cov.: 33

Gnomad AFR AF: 0.506

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.299

Gnomad ASJ AF: 0.213

Gnomad EAS AF: 0.505

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.268

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

GnomAD4 genome AF: 0.288 AC: 43808 AN: 152104 Hom.: 8117 Cov.: 33 AF XY: 0.295 AC XY: 21934 AN XY: 74376

Gnomad4 AFR AF: 0.507

Gnomad4 AMR AF: 0.300

Gnomad4 ASJ AF: 0.213

Gnomad4 EAS AF: 0.504

Gnomad4 SAS AF: 0.252

Gnomad4 FIN AF: 0.249

Gnomad4 NFE AF: 0.150

Gnomad4 OTH AF: 0.265

Alfa AF: 0.175 Hom.: 3741

Bravo AF: 0.299

Asia WGS AF: 0.358 AC: 1247 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	2.1
DANN	Benign	0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs8126757; hg19: chr21-46848282;