rs61731167

Positions:

• chr21-45489512-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.1950G>A​(p.Pro650=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0645 in 1,599,814 control chromosomes in the GnomAD database, including 3,930 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (348 hom., cov: 32)
  • Exomes 𝑓: 0.065 (3582 hom.)
• Consequence: COL18A1 NM_001379500.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -5.99

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=-0.92).
• BP6: Variant 21-45489512-G-A is Benign according to our data. Variant chr21-45489512-G-A is described in ClinVar as [Benign]. Clinvar id is 261896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45489512-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-5.99 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0914 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.1950G>A	p.Pro650=	synonymous_variant	19/42	ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3	c.3195G>A	p.Pro1065=	synonymous_variant	18/41		NP_569711.2
COL18A1	NM_030582.4	c.2490G>A	p.Pro830=	synonymous_variant	18/41		NP_085059.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.1950G>A	p.Pro650=	synonymous_variant	19/42		NM_001379500.1	ENSP00000498485
COL18A1	ENST00000355480.10	c.2490G>A	p.Pro830=	synonymous_variant	18/41	1		ENSP00000347665
COL18A1	ENST00000359759.8	c.3195G>A	p.Pro1065=	synonymous_variant	18/41	5		ENSP00000352798	P1

Frequencies

GnomAD3 genomes AF: 0.0582 AC: 8856 AN: 152116 Hom.: 349 Cov.: 32

Gnomad AFR AF: 0.0271

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.0394

Gnomad ASJ AF: 0.0599

Gnomad EAS AF: 0.00753

Gnomad SAS AF: 0.0985

Gnomad FIN AF: 0.158

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0664

Gnomad OTH AF: 0.0522

GnomAD3 exomes AF: 0.0653 AC: 14887 AN: 227988 Hom.: 690 AF XY: 0.0687 AC XY: 8554 AN XY: 124590

Gnomad AFR exome AF: 0.0263

Gnomad AMR exome AF: 0.0257

Gnomad ASJ exome AF: 0.0680

Gnomad EAS exome AF: 0.0106

Gnomad SAS exome AF: 0.100

Gnomad FIN exome AF: 0.145

Gnomad NFE exome AF: 0.0676

Gnomad OTH exome AF: 0.0618

GnomAD4 exome AF: 0.0652 AC: 94316 AN: 1447580 Hom.: 3582 Cov.: 30 AF XY: 0.0666 AC XY: 47913 AN XY: 719110

Gnomad4 AFR exome AF: 0.0277

Gnomad4 AMR exome AF: 0.0261

Gnomad4 ASJ exome AF: 0.0656

Gnomad4 EAS exome AF: 0.00519

Gnomad4 SAS exome AF: 0.102

Gnomad4 FIN exome AF: 0.135

Gnomad4 NFE exome AF: 0.0644

Gnomad4 OTH exome AF: 0.0569

GnomAD4 genome AF: 0.0583 AC: 8873 AN: 152234 Hom.: 348 Cov.: 32 AF XY: 0.0632 AC XY: 4701 AN XY: 74420

Gnomad4 AFR AF: 0.0274

Gnomad4 AMR AF: 0.0393

Gnomad4 ASJ AF: 0.0599

Gnomad4 EAS AF: 0.00774

Gnomad4 SAS AF: 0.0988

Gnomad4 FIN AF: 0.158

Gnomad4 NFE AF: 0.0664

Gnomad4 OTH AF: 0.0521

Alfa AF: 0.0601 Hom.: 114

Bravo AF: 0.0472

Asia WGS AF: 0.0440 AC: 156 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

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	-0.92
CADD	Benign	0.12
DANN	Benign	0.66
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8

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: rs61731167; hg19: chr21-46909426;