chr21-45481557-A-G

Position:

• chr21-45481557-A-G

Variant summary

Our verdict is Benign. Variant got -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

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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.633 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.1612-406A>G		intron_variant		ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3	c.2857-406A>G		intron_variant			NP_569711.2
COL18A1	NM_030582.4	c.2152-406A>G		intron_variant			NP_085059.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.1612-406A>G		intron_variant			NM_001379500.1	ENSP00000498485.1
COL18A1	ENST00000355480.10	c.2152-406A>G		intron_variant		1		ENSP00000347665.5
COL18A1	ENST00000359759.8	c.2857-406A>G		intron_variant		5		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

Gnomad4 AFR AF: 0.639

Gnomad4 AMR AF: 0.421

Gnomad4 ASJ AF: 0.470

Gnomad4 EAS AF: 0.472

Gnomad4 SAS AF: 0.390

Gnomad4 FIN AF: 0.338

Gnomad4 NFE AF: 0.379

Gnomad4 OTH AF: 0.458

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.0
DANN	Benign	0.18

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

Publications

LitVar

Other links and lift over

dbSNP: rs3818661; hg19: chr21-46901471;