21-45487373-C-T

Variant names:

• chr21-45487373-C-T
• rs9977268
• NM_001379500.1:c.1834-74C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001379500.1(COL18A1):​c.1834-74C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 1,549,714 control chromosomes in the GnomAD database, including 28,643 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2324 hom., cov: 33)
  • Exomes 𝑓: 0.19 (26319 hom.)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.356
• Publications: 19 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 21-45487373-C-T is Benign according to our data. Variant chr21-45487373-C-T is described in ClinVar as Benign. ClinVar VariationId is 1263852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.197 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.1834-74C>T		intron	N/A	NP_001366429.1
	COL18A1	NM_130444.3		c.3079-74C>T		intron	N/A	NP_569711.2
	COL18A1	NM_030582.4		c.2374-74C>T		intron	N/A	NP_085059.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.1834-74C>T		intron	N/A	ENSP00000498485.1
	COL18A1	ENST00000355480.10	TSL:1	c.2374-74C>T		intron	N/A	ENSP00000347665.5
	COL18A1	ENST00000359759.8	TSL:5	c.3079-74C>T		intron	N/A	ENSP00000352798.4

Frequencies

GnomAD3 genomes AF: 0.171 AC: 25944 AN: 152106 Hom.: 2326 Cov.: 33

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.203

Gnomad ASJ AF: 0.243

Gnomad EAS AF: 0.139

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.193

GnomAD4 exome AF: 0.192 AC: 268674 AN: 1397490 Hom.: 26319 AF XY: 0.192 AC XY: 133893 AN XY: 698242

African (AFR) AF: 0.106 AC: 3417 AN: 32330

American (AMR) AF: 0.207 AC: 9123 AN: 44052

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 6438 AN: 25702

East Asian (EAS) AF: 0.122 AC: 4810 AN: 39320

South Asian (SAS) AF: 0.160 AC: 13555 AN: 84680

European-Finnish (FIN) AF: 0.167 AC: 7582 AN: 45414

Middle Eastern (MID) AF: 0.212 AC: 901 AN: 4260

European-Non Finnish (NFE) AF: 0.199 AC: 211994 AN: 1063482

Other (OTH) AF: 0.186 AC: 10854 AN: 58250

GnomAD4 genome AF: 0.170 AC: 25938 AN: 152224 Hom.: 2324 Cov.: 33 AF XY: 0.171 AC XY: 12697 AN XY: 74426

African (AFR) AF: 0.109 AC: 4510 AN: 41554

American (AMR) AF: 0.202 AC: 3092 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 842 AN: 3472

East Asian (EAS) AF: 0.139 AC: 720 AN: 5168

South Asian (SAS) AF: 0.162 AC: 782 AN: 4828

European-Finnish (FIN) AF: 0.178 AC: 1888 AN: 10614

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.199 AC: 13554 AN: 67972

Other (OTH) AF: 0.192 AC: 405 AN: 2108

Alfa AF: 0.196 Hom.: 2942

Bravo AF: 0.171

Asia WGS AF: 0.164 AC: 572 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

May 10, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.9
DANN	Benign	0.57
PhyloP100		0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs9977268; hg19: chr21-46907287; COSMIC: COSV60587554; COSMIC: COSV60587554;