chr21-45473986-G-A

Variant names:

• chr21-45473986-G-A
• rs1555859077
• NM_001379500.1:c.738+5G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001379500.1(COL18A1):​c.738+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000000699 in 1,431,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: COL18A1 NM_001379500.1 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.08
• Publications: 0 publications found

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 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.738+5G>A		splice_region_variant, intron_variant	Intron 4 of 41	ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3	c.1983+5G>A		splice_region_variant, intron_variant	Intron 3 of 40		NP_569711.2
COL18A1	NM_030582.4	c.1278+5G>A		splice_region_variant, intron_variant	Intron 3 of 40		NP_085059.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.738+5G>A		splice_region_variant, intron_variant	Intron 4 of 41		NM_001379500.1	ENSP00000498485.1
COL18A1	ENST00000355480.10	c.1278+5G>A		splice_region_variant, intron_variant	Intron 3 of 40	1		ENSP00000347665.5
COL18A1	ENST00000359759.8	c.1983+5G>A		splice_region_variant, intron_variant	Intron 3 of 40	5		ENSP00000352798.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1431280 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 709674

African (AFR) AF: 0.00 AC: 0 AN: 32732

American (AMR) AF: 0.00 AC: 0 AN: 40968

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25586

East Asian (EAS) AF: 0.00 AC: 0 AN: 37910

South Asian (SAS) AF: 0.00 AC: 0 AN: 81950

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51172

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 9.12e-7 AC: 1 AN: 1095990

Other (OTH) AF: 0.00 AC: 0 AN: 59228

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	22
DANN	Benign	0.88
PhyloP100		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.93		Position offset: -5

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

Other links and lift over

dbSNP: rs1555859077; hg19: chr21-46893900;