rs2838920

Positions:

• chr21-45421483-G-A

Variant summary

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

The NM_001379500.1(COL18A1):​c.106+16010G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 534,456 control chromosomes in the GnomAD database, including 5,777 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 (2490 hom., cov: 33)
  • Exomes 𝑓: 0.12 (3287 hom.)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.03

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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.275 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.106+16010G>A		intron_variant		ENST00000651438.1	NP_001366429.1
COL18A1-AS1	NR_027498.1	n.574C>T		non_coding_transcript_exon_variant	3/3
COL18A1-AS1	NR_028082.1	n.1658C>T		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.106+16010G>A		intron_variant			NM_001379500.1	ENSP00000498485.1
COL18A1-AS1	ENST00000397787.5	n.1658C>T		non_coding_transcript_exon_variant	3/3	1
COL18A1-AS1	ENST00000485206.1	n.574C>T		non_coding_transcript_exon_variant	3/3	1

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24485 AN: 152108 Hom.: 2488 Cov.: 33

Gnomad AFR AF: 0.279

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.257

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.0994

Gnomad OTH AF: 0.160

GnomAD3 exomes AF: 0.136 AC: 34047 AN: 251026 Hom.: 2811 AF XY: 0.132 AC XY: 17903 AN XY: 135828

Gnomad AFR exome AF: 0.282

Gnomad AMR exome AF: 0.128

Gnomad ASJ exome AF: 0.124

Gnomad EAS exome AF: 0.287

Gnomad SAS exome AF: 0.132

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.0990

Gnomad OTH exome AF: 0.122

GnomAD4 exome AF: 0.121 AC: 46283 AN: 382230 Hom.: 3287 Cov.: 0 AF XY: 0.121 AC XY: 26308 AN XY: 217608

Gnomad4 AFR exome AF: 0.277

Gnomad4 AMR exome AF: 0.128

Gnomad4 ASJ exome AF: 0.123

Gnomad4 EAS exome AF: 0.279

Gnomad4 SAS exome AF: 0.131

Gnomad4 FIN exome AF: 0.117

Gnomad4 NFE exome AF: 0.0963

Gnomad4 OTH exome AF: 0.131

GnomAD4 genome AF: 0.161 AC: 24511 AN: 152226 Hom.: 2490 Cov.: 33 AF XY: 0.163 AC XY: 12098 AN XY: 74424

Gnomad4 AFR AF: 0.279

Gnomad4 AMR AF: 0.127

Gnomad4 ASJ AF: 0.137

Gnomad4 EAS AF: 0.257

Gnomad4 SAS AF: 0.131

Gnomad4 FIN AF: 0.126

Gnomad4 NFE AF: 0.0994

Gnomad4 OTH AF: 0.159

Alfa AF: 0.114 Hom.: 1727

Bravo AF: 0.167

Asia WGS AF: 0.202 AC: 704 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.44
DANN	Benign	0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2838920; hg19: chr21-46841398; COSMIC: COSV67268553;