chr21-45419710-G-T

Position:

• chr21-45419710-G-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+14237G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.689 in 152,112 control chromosomes in the GnomAD database, including 37,878 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 0.69 (37878 hom., cov: 34)
  • Exomes 𝑓: 0.71 (4 hom.)
  • Failed GnomAD Quality Control
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.404

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-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.05).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.802 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.106+14237G>T		intron_variant		ENST00000651438.1	NP_001366429.1
COL18A1-AS1	NR_027498.1	n.*6C>A		downstream_gene_variant
COL18A1-AS1	NR_028082.1	n.*6C>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.106+14237G>T		intron_variant			NM_001379500.1	ENSP00000498485.1
COL18A1-AS1	ENST00000397787.5	n.*6C>A		downstream_gene_variant		1
COL18A1-AS1	ENST00000485206.1	n.*6C>A		downstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.689 AC: 104792 AN: 151994 Hom.: 37876 Cov.: 34

Gnomad AFR AF: 0.475

Gnomad AMI AF: 0.760

Gnomad AMR AF: 0.659

Gnomad ASJ AF: 0.839

Gnomad EAS AF: 0.495

Gnomad SAS AF: 0.729

Gnomad FIN AF: 0.825

Gnomad MID AF: 0.796

Gnomad NFE AF: 0.808

Gnomad OTH AF: 0.701

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.714 AC: 10 AN: 14 Hom.: 4 Cov.: 0 AF XY: 0.875 AC XY: 7 AN XY: 8

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 0.600

Gnomad4 OTH exome AF: 1.00

GnomAD4 genome AF: 0.689 AC: 104827 AN: 152112 Hom.: 37878 Cov.: 34 AF XY: 0.687 AC XY: 51113 AN XY: 74378

Gnomad4 AFR AF: 0.475

Gnomad4 AMR AF: 0.658

Gnomad4 ASJ AF: 0.839

Gnomad4 EAS AF: 0.495

Gnomad4 SAS AF: 0.730

Gnomad4 FIN AF: 0.825

Gnomad4 NFE AF: 0.808

Gnomad4 OTH AF: 0.704

Alfa AF: 0.788 Hom.: 45251

Bravo AF: 0.669

Asia WGS AF: 0.615 AC: 2138 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.19
DANN	Benign	0.23

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2838916; hg19: chr21-46839625;