rs17338853

Positions:

• chr21-45476467-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001379500.1(COL18A1):​c.915G>T​(p.Val305=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0368 in 1,608,854 control chromosomes in the GnomAD database, including 1,220 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (85 hom., cov: 33)
  • Exomes 𝑓: 0.038 (1135 hom.)
• Consequence: COL18A1 NM_001379500.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0710

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 21-45476467-G-T is Benign according to our data. Variant chr21-45476467-G-T is described in ClinVar as [Benign]. Clinvar id is 261888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45476467-G-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.071 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0278 (4236/152248) while in subpopulation NFE AF= 0.0419 (2849/68014). AF 95% confidence interval is 0.0406. There are 85 homozygotes in gnomad4. There are 1993 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 85 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL18A1	NM_001379500.1	c.915G>T	p.Val305=	synonymous_variant	6/42	ENST00000651438.1
COL18A1	NM_130444.3	c.2160G>T	p.Val720=	synonymous_variant	5/41
COL18A1	NM_030582.4	c.1455G>T	p.Val485=	synonymous_variant	5/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL18A1	ENST00000651438.1	c.915G>T	p.Val305=	synonymous_variant	6/42		NM_001379500.1
COL18A1	ENST00000355480.10	c.1455G>T	p.Val485=	synonymous_variant	5/41	1
COL18A1	ENST00000359759.8	c.2160G>T	p.Val720=	synonymous_variant	5/41	5		P1

Frequencies

GnomAD3 genomes AF: 0.0279 AC: 4240 AN: 152130 Hom.: 84 Cov.: 33

Gnomad AFR AF: 0.00763

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0347

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.00789

Gnomad SAS AF: 0.0372

Gnomad FIN AF: 0.0140

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0419

Gnomad OTH AF: 0.0296

GnomAD3 exomes AF: 0.0322 AC: 7556 AN: 234672 Hom.: 147 AF XY: 0.0330 AC XY: 4223 AN XY: 127976

Gnomad AFR exome AF: 0.00722

Gnomad AMR exome AF: 0.0297

Gnomad ASJ exome AF: 0.0184

Gnomad EAS exome AF: 0.00716

Gnomad SAS exome AF: 0.0362

Gnomad FIN exome AF: 0.0183

Gnomad NFE exome AF: 0.0428

Gnomad OTH exome AF: 0.0368

GnomAD4 exome AF: 0.0378 AC: 55034 AN: 1456606 Hom.: 1135 Cov.: 33 AF XY: 0.0379 AC XY: 27464 AN XY: 724168

Gnomad4 AFR exome AF: 0.00638

Gnomad4 AMR exome AF: 0.0318

Gnomad4 ASJ exome AF: 0.0189

Gnomad4 EAS exome AF: 0.00968

Gnomad4 SAS exome AF: 0.0357

Gnomad4 FIN exome AF: 0.0182

Gnomad4 NFE exome AF: 0.0416

Gnomad4 OTH exome AF: 0.0364

GnomAD4 genome AF: 0.0278 AC: 4236 AN: 152248 Hom.: 85 Cov.: 33 AF XY: 0.0268 AC XY: 1993 AN XY: 74450

Gnomad4 AFR AF: 0.00761

Gnomad4 AMR AF: 0.0344

Gnomad4 ASJ AF: 0.0225

Gnomad4 EAS AF: 0.00791

Gnomad4 SAS AF: 0.0379

Gnomad4 FIN AF: 0.0140

Gnomad4 NFE AF: 0.0419

Gnomad4 OTH AF: 0.0288

Alfa AF: 0.0390 Hom.: 152

Bravo AF: 0.0288

Asia WGS AF: 0.0270 AC: 95 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Knobloch syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.38
DANN	Benign	0.50
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs17338853; hg19: chr21-46896381;