21-45454831-T-G

Variant names:

• chr21-45454831-T-G
• rs755548
• NM_001379500.1:c.107-13411T>G

Variant summary

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

The NM_001379500.1(COL18A1):​c.107-13411T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.439 in 151,816 control chromosomes in the GnomAD database, including 16,210 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 0.44 (16210 hom., cov: 33)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.701
• Publications: 6 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: 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 = 0.657 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379500.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	NM_001379500.1	MANE Select	c.107-13411T>G		intron	N/A	NP_001366429.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.107-13411T>G		intron	N/A	ENSP00000498485.1
	COL18A1	ENST00000859062.1		c.107-914T>G		intron	N/A	ENSP00000529121.1
	COL18A1	ENST00000930602.1		c.107-13411T>G		intron	N/A	ENSP00000600661.1

Frequencies

GnomAD3 genomes AF: 0.439 AC: 66609 AN: 151698 Hom.: 16183 Cov.: 33

Gnomad AFR AF: 0.664

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.389

Gnomad ASJ AF: 0.437

Gnomad EAS AF: 0.464

Gnomad SAS AF: 0.360

Gnomad FIN AF: 0.330

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.337

Gnomad OTH AF: 0.431

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.439 AC: 66679 AN: 151816 Hom.: 16210 Cov.: 33 AF XY: 0.439 AC XY: 32583 AN XY: 74170

African (AFR) AF: 0.664 AC: 27502 AN: 41440

American (AMR) AF: 0.388 AC: 5928 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.437 AC: 1514 AN: 3466

East Asian (EAS) AF: 0.464 AC: 2388 AN: 5142

South Asian (SAS) AF: 0.361 AC: 1735 AN: 4812

European-Finnish (FIN) AF: 0.330 AC: 3467 AN: 10520

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.337 AC: 22887 AN: 67858

Other (OTH) AF: 0.430 AC: 909 AN: 2114

Alfa AF: 0.242 Hom.: 637

Bravo AF: 0.454

Asia WGS AF: 0.423 AC: 1473 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.3
DANN	Benign	0.41
PhyloP100		-0.70
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: rs755548; hg19: chr21-46874745;