rs9979845

Positions:

• chr21-45480033-G-A
• chr21-45480033-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001379500.1(COL18A1):​c.1312-37G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.223 in 1,610,918 control chromosomes in the GnomAD database, including 41,142 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (2993 hom., cov: 31)
  • Exomes 𝑓: 0.23 (38149 hom.)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.578

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 21-45480033-G-A is Benign according to our data. Variant chr21-45480033-G-A is described in ClinVar as [Benign]. Clinvar id is 261890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.1312-37G>A		intron_variant		ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3	c.2557-37G>A		intron_variant			NP_569711.2
COL18A1	NM_030582.4	c.1852-37G>A		intron_variant			NP_085059.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.1312-37G>A		intron_variant			NM_001379500.1	ENSP00000498485.1
COL18A1	ENST00000355480.10	c.1852-37G>A		intron_variant		1		ENSP00000347665.5
COL18A1	ENST00000359759.8	c.2557-37G>A		intron_variant		5		ENSP00000352798.4

Frequencies

GnomAD3 genomes AF: 0.193 AC: 29336 AN: 151652 Hom.: 2993 Cov.: 31

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.257

Gnomad EAS AF: 0.139

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.208

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.234

Gnomad OTH AF: 0.216

GnomAD3 exomes AF: 0.209 AC: 51649 AN: 247158 Hom.: 5598 AF XY: 0.210 AC XY: 28158 AN XY: 134292

Gnomad AFR exome AF: 0.115

Gnomad AMR exome AF: 0.217

Gnomad ASJ exome AF: 0.259

Gnomad EAS exome AF: 0.140

Gnomad SAS exome AF: 0.180

Gnomad FIN exome AF: 0.207

Gnomad NFE exome AF: 0.234

Gnomad OTH exome AF: 0.218

GnomAD4 exome AF: 0.226 AC: 330462 AN: 1459150 Hom.: 38149 Cov.: 33 AF XY: 0.226 AC XY: 163878 AN XY: 726084

Gnomad4 AFR exome AF: 0.110

Gnomad4 AMR exome AF: 0.221

Gnomad4 ASJ exome AF: 0.266

Gnomad4 EAS exome AF: 0.123

Gnomad4 SAS exome AF: 0.182

Gnomad4 FIN exome AF: 0.203

Gnomad4 NFE exome AF: 0.238

Gnomad4 OTH exome AF: 0.215

GnomAD4 genome AF: 0.193 AC: 29339 AN: 151768 Hom.: 2993 Cov.: 31 AF XY: 0.194 AC XY: 14370 AN XY: 74178

Gnomad4 AFR AF: 0.115

Gnomad4 AMR AF: 0.224

Gnomad4 ASJ AF: 0.257

Gnomad4 EAS AF: 0.139

Gnomad4 SAS AF: 0.183

Gnomad4 FIN AF: 0.208

Gnomad4 NFE AF: 0.234

Gnomad4 OTH AF: 0.214

Alfa AF: 0.156 Hom.: 408

Bravo AF: 0.192

Asia WGS AF: 0.172 AC: 598 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Glaucoma, primary closed-angle Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Knobloch syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	6.4
DANN	Benign	0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs9979845; hg19: chr21-46899947; COSMIC: COSV62702155; COSMIC: COSV62702155;