rs8131523

Positions:

• chr21-45422528-C-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+17055C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 520,730 control chromosomes in the GnomAD database, including 5,299 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 0.16 (2454 hom., cov: 33)
  • Exomes 𝑓: 0.12 (2845 hom.)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.187

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:23132): (COL18A1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL18A1	NM_001379500.1	c.106+17055C>T		intron_variant		ENST00000651438.1
COL18A1-AS1	NR_027498.1	n.321G>A		non_coding_transcript_exon_variant	2/3
COL18A1-AS1	NR_028082.1	n.1405G>A		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL18A1	ENST00000651438.1	c.106+17055C>T		intron_variant			NM_001379500.1
COL18A1-AS1	ENST00000397787.5	n.1405G>A		non_coding_transcript_exon_variant	2/3	1
COL18A1-AS1	ENST00000485206.1	n.321G>A		non_coding_transcript_exon_variant	2/3	1

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24263 AN: 152118 Hom.: 2454 Cov.: 33

Gnomad AFR AF: 0.281

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.216

Gnomad SAS AF: 0.121

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.0995

Gnomad OTH AF: 0.158

GnomAD3 exomes AF: 0.129 AC: 28582 AN: 221864 Hom.: 2102 AF XY: 0.125 AC XY: 15052 AN XY: 120042

Gnomad AFR exome AF: 0.279

Gnomad AMR exome AF: 0.126

Gnomad ASJ exome AF: 0.123

Gnomad EAS exome AF: 0.227

Gnomad SAS exome AF: 0.122

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.0984

Gnomad OTH exome AF: 0.119

GnomAD4 exome AF: 0.116 AC: 42910 AN: 368494 Hom.: 2845 Cov.: 0 AF XY: 0.116 AC XY: 24294 AN XY: 209438

Gnomad4 AFR exome AF: 0.276

Gnomad4 AMR exome AF: 0.126

Gnomad4 ASJ exome AF: 0.122

Gnomad4 EAS exome AF: 0.219

Gnomad4 SAS exome AF: 0.122

Gnomad4 FIN exome AF: 0.116

Gnomad4 NFE exome AF: 0.0954

Gnomad4 OTH exome AF: 0.128

GnomAD4 genome AF: 0.160 AC: 24283 AN: 152236 Hom.: 2454 Cov.: 33 AF XY: 0.161 AC XY: 11982 AN XY: 74438

Gnomad4 AFR AF: 0.280

Gnomad4 AMR AF: 0.127

Gnomad4 ASJ AF: 0.136

Gnomad4 EAS AF: 0.216

Gnomad4 SAS AF: 0.122

Gnomad4 FIN AF: 0.126

Gnomad4 NFE AF: 0.0995

Gnomad4 OTH AF: 0.157

Alfa AF: 0.121 Hom.: 818

Bravo AF: 0.165

Asia WGS AF: 0.168 AC: 586 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.5
DANN	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs8131523; hg19: chr21-46842443;