rs8131523

Variant names:

• chr21-45422528-C-T
• rs8131523
• ENST00000397787.5:n.1405G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000397787.5(COL18A1-AS1):​n.1405G>A variant causes a non coding transcript exon 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-AS1 ENST00000397787.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.187
• Publications: 9 publications found

Genes affected

COL18A1-AS1 (HGNC:23132): (COL18A1 antisense RNA 1)

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=-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 rank	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.106+17055C>T		intron_variant	Intron 2 of 41	ENST00000651438.1	NP_001366429.1
COL18A1-AS1	NR_027498.1	n.321G>A		non_coding_transcript_exon_variant	Exon 2 of 3
COL18A1-AS1	NR_028082.1	n.1405G>A		non_coding_transcript_exon_variant	Exon 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL18A1-AS1	ENST00000397787.5	n.1405G>A		non_coding_transcript_exon_variant	Exon 2 of 3	1
COL18A1-AS1	ENST00000485206.1	n.321G>A		non_coding_transcript_exon_variant	Exon 2 of 3	1
COL18A1	ENST00000651438.1	c.106+17055C>T		intron_variant	Intron 2 of 41		NM_001379500.1	ENSP00000498485.1

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

GnomAD2 exomes AF: 0.129 AC: 28582 AN: 221864 AF XY: 0.125

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 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

African (AFR) AF: 0.276 AC: 2863 AN: 10390

American (AMR) AF: 0.126 AC: 4253 AN: 33848

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 1389 AN: 11370

East Asian (EAS) AF: 0.219 AC: 2776 AN: 12692

South Asian (SAS) AF: 0.122 AC: 7839 AN: 64450

European-Finnish (FIN) AF: 0.116 AC: 3502 AN: 30270

Middle Eastern (MID) AF: 0.148 AC: 418 AN: 2828

European-Non Finnish (NFE) AF: 0.0954 AC: 17791 AN: 186446

Other (OTH) AF: 0.128 AC: 2079 AN: 16200

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

African (AFR) AF: 0.280 AC: 11641 AN: 41526

American (AMR) AF: 0.127 AC: 1936 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 472 AN: 3470

East Asian (EAS) AF: 0.216 AC: 1115 AN: 5174

South Asian (SAS) AF: 0.122 AC: 587 AN: 4830

European-Finnish (FIN) AF: 0.126 AC: 1333 AN: 10612

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.0995 AC: 6765 AN: 68000

Other (OTH) AF: 0.157 AC: 331 AN: 2114

Alfa AF: 0.121 Hom.: 913

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
PhyloP100		-0.19
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
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: rs8131523; hg19: chr21-46842443;