21-45482789-G-A

Position:

• chr21-45482789-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001379500.1(COL18A1):​c.1675-6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0025 in 1,614,160 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (12 hom.)
• Consequence: COL18A1 NM_001379500.1 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.583

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 21-45482789-G-A is Benign according to our data. Variant chr21-45482789-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 261893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45482789-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.1675-6G>A		splice_region_variant, intron_variant		ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3	c.2920-6G>A		splice_region_variant, intron_variant			NP_569711.2
COL18A1	NM_030582.4	c.2215-6G>A		splice_region_variant, intron_variant			NP_085059.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.1675-6G>A		splice_region_variant, intron_variant			NM_001379500.1	ENSP00000498485.1
COL18A1	ENST00000355480.10	c.2215-6G>A		splice_region_variant, intron_variant		1		ENSP00000347665.5
COL18A1	ENST00000359759.8	c.2920-6G>A		splice_region_variant, intron_variant		5		ENSP00000352798.4

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 412 AN: 152160 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00851

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00294

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00311 AC: 777 AN: 249542 Hom.: 4 AF XY: 0.00321 AC XY: 434 AN XY: 135400

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.00501

Gnomad ASJ exome AF: 0.0127

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00124

Gnomad FIN exome AF: 0.000557

Gnomad NFE exome AF: 0.00343

Gnomad OTH exome AF: 0.00478

GnomAD4 exome AF: 0.00247 AC: 3618 AN: 1461882 Hom.: 12 Cov.: 31 AF XY: 0.00260 AC XY: 1892 AN XY: 727244

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.00456

Gnomad4 ASJ exome AF: 0.0120

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00139

Gnomad4 FIN exome AF: 0.000674

Gnomad4 NFE exome AF: 0.00239

Gnomad4 OTH exome AF: 0.00328

GnomAD4 genome AF: 0.00271 AC: 412 AN: 152278 Hom.: 6 Cov.: 33 AF XY: 0.00285 AC XY: 212 AN XY: 74460

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00850

Gnomad4 ASJ AF: 0.00979

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00294

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00317 Hom.: 0

Bravo AF: 0.00290

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00540

EpiControl AF: 0.00421

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	COL18A1: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 21, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Knobloch syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.0
DANN	Benign	0.44

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

Publications

LitVar

Other links and lift over

dbSNP: rs142726108; hg19: chr21-46902703; COSMIC: COSV62699489; COSMIC: COSV62699489;