21-45428241-C-T

Variant names:

• chr21-45428241-C-T
• rs11911327
• NM_001379500.1:c.106+22768C>T

Variant summary

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

The NM_001379500.1(COL18A1):​c.106+22768C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0394 in 152,174 control chromosomes in the GnomAD database, including 318 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 0.039 (318 hom., cov: 33)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.62
• Publications: 3 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.184 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	NM_001379500.1	MANE Select	c.106+22768C>T		intron	N/A	NP_001366429.1	P39060-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.106+22768C>T		intron	N/A	ENSP00000498485.1	P39060-2
	COL18A1	ENST00000859062.1		c.106+22768C>T		intron	N/A	ENSP00000529121.1
	COL18A1	ENST00000930602.1		c.106+22768C>T		intron	N/A	ENSP00000600661.1

Frequencies

GnomAD3 genomes AF: 0.0393 AC: 5976 AN: 152056 Hom.: 314 Cov.: 33

Gnomad AFR AF: 0.0320

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.0234

Gnomad EAS AF: 0.194

Gnomad SAS AF: 0.0522

Gnomad FIN AF: 0.0342

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0139

Gnomad OTH AF: 0.0349

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

GnomAD4 genome AF: 0.0394 AC: 5993 AN: 152174 Hom.: 318 Cov.: 33 AF XY: 0.0428 AC XY: 3185 AN XY: 74386

African (AFR) AF: 0.0320 AC: 1328 AN: 41530

American (AMR) AF: 0.127 AC: 1945 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0234 AC: 81 AN: 3468

East Asian (EAS) AF: 0.194 AC: 995 AN: 5130

South Asian (SAS) AF: 0.0520 AC: 251 AN: 4826

European-Finnish (FIN) AF: 0.0342 AC: 363 AN: 10602

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0139 AC: 942 AN: 68006

Other (OTH) AF: 0.0350 AC: 74 AN: 2116

Alfa AF: 0.0368 Hom.: 49

Bravo AF: 0.0454

Asia WGS AF: 0.111 AC: 386 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.18
DANN	Benign	0.57
PhyloP100		-1.6
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		1.8
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: rs11911327; hg19: chr21-46848156;