rs2230689

chr21-45477887-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001379500.1(COL18A1):c.1143G>A(p.Ala381=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00835 in 1,562,254 control chromosomes in the GnomAD database, including 275 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A381A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0069 (30 hom., cov: 33)
  • Exomes 𝑓: 0.0085 (245 hom.)
• Consequence: COL18A1 NM_001379500.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.773

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=-0.81).
• BP6: Variant 21-45477887-G-A is Benign according to our data. Variant chr21-45477887-G-A is described in ClinVar as [Benign]. Clinvar id is 261889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45477887-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.773 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0698 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL18A1	NM_001379500.1	c.1143G>A	p.Ala381=	synonymous_variant	8/42	ENST00000651438.1
COL18A1	NM_130444.3	c.2388G>A	p.Ala796=	synonymous_variant	7/41
COL18A1	NM_030582.4	c.1683G>A	p.Ala561=	synonymous_variant	7/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL18A1	ENST00000651438.1	c.1143G>A	p.Ala381=	synonymous_variant	8/42		NM_001379500.1
COL18A1	ENST00000355480.10	c.1683G>A	p.Ala561=	synonymous_variant	7/41	1
COL18A1	ENST00000359759.8	c.2388G>A	p.Ala796=	synonymous_variant	7/41	5		P1

Frequencies

GnomAD3 genomes AF: 0.00690 AC: 1050 AN: 152208 Hom.: 30 Cov.: 33

Gnomad AFR AF: 0.00166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0763

Gnomad SAS AF: 0.0449

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00426

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.0142 AC: 2402 AN: 169700 Hom.: 77 AF XY: 0.0154 AC XY: 1407 AN XY: 91126

Gnomad AFR exome AF: 0.000789

Gnomad AMR exome AF: 0.00157

Gnomad ASJ exome AF: 0.00161

Gnomad EAS exome AF: 0.0861

Gnomad SAS exome AF: 0.0397

Gnomad FIN exome AF: 0.00155

Gnomad NFE exome AF: 0.00420

Gnomad OTH exome AF: 0.00648

GnomAD4 exome AF: 0.00851 AC: 11995 AN: 1409928 Hom.: 245 Cov.: 32 AF XY: 0.00922 AC XY: 6427 AN XY: 696882

Gnomad4 AFR exome AF: 0.000936

Gnomad4 AMR exome AF: 0.00154

Gnomad4 ASJ exome AF: 0.00178

Gnomad4 EAS exome AF: 0.0877

Gnomad4 SAS exome AF: 0.0383

Gnomad4 FIN exome AF: 0.00120

Gnomad4 NFE exome AF: 0.00457

Gnomad4 OTH exome AF: 0.00977

GnomAD4 genome AF: 0.00687 AC: 1046 AN: 152326 Hom.: 30 Cov.: 33 AF XY: 0.00777 AC XY: 579 AN XY: 74480

Gnomad4 AFR AF: 0.00166

Gnomad4 AMR AF: 0.00372

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0760

Gnomad4 SAS AF: 0.0445

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00426

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00434 Hom.: 3

Bravo AF: 0.00603

Asia WGS AF: 0.0480 AC: 166 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Knobloch syndrome Benign:1

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 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	-0.81
Cadd	Benign	5.8
Dann	Benign	0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs2230689; hg19: chr21-46897801; COSMIC: COSV62702101; COSMIC: COSV62702101;