rs73370824

Positions:

• chr21-45487424-C-A
• chr21-45487424-C-T

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.1834-23C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0717 in 1,611,454 control chromosomes in the GnomAD database, including 5,666 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.11 (1331 hom., cov: 33)
  • Exomes 𝑓: 0.068 (4335 hom.)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.20

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: This place is a probable branch point but likely benign (scored 1 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 21-45487424-C-A is Benign according to our data. Variant chr21-45487424-C-A is described in ClinVar as [Benign]. Clinvar id is 261894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45487424-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.221 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL18A1	NM_001379500.1	c.1834-23C>A		intron_variant		ENST00000651438.1
COL18A1	NM_030582.4	c.2374-23C>A		intron_variant
COL18A1	NM_130444.3	c.3079-23C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL18A1	ENST00000651438.1	c.1834-23C>A		intron_variant			NM_001379500.1
COL18A1	ENST00000355480.10	c.2374-23C>A		intron_variant		1
COL18A1	ENST00000359759.8	c.3079-23C>A		intron_variant		5		P1

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16339 AN: 152124 Hom.: 1330 Cov.: 33

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0778

Gnomad ASJ AF: 0.0516

Gnomad EAS AF: 0.0998

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.0160

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0617

Gnomad OTH AF: 0.0942

GnomAD3 exomes AF: 0.0730 AC: 18099 AN: 247794 Hom.: 992 AF XY: 0.0719 AC XY: 9689 AN XY: 134728

Gnomad AFR exome AF: 0.228

Gnomad AMR exome AF: 0.0503

Gnomad ASJ exome AF: 0.0480

Gnomad EAS exome AF: 0.0959

Gnomad SAS exome AF: 0.0982

Gnomad FIN exome AF: 0.0199

Gnomad NFE exome AF: 0.0607

Gnomad OTH exome AF: 0.0669

GnomAD4 exome AF: 0.0679 AC: 99141 AN: 1459212 Hom.: 4335 Cov.: 33 AF XY: 0.0682 AC XY: 49529 AN XY: 725924

Gnomad4 AFR exome AF: 0.235

Gnomad4 AMR exome AF: 0.0549

Gnomad4 ASJ exome AF: 0.0477

Gnomad4 EAS exome AF: 0.139

Gnomad4 SAS exome AF: 0.0945

Gnomad4 FIN exome AF: 0.0202

Gnomad4 NFE exome AF: 0.0609

Gnomad4 OTH exome AF: 0.0788

GnomAD4 genome AF: 0.107 AC: 16351 AN: 152242 Hom.: 1331 Cov.: 33 AF XY: 0.104 AC XY: 7739 AN XY: 74442

Gnomad4 AFR AF: 0.225

Gnomad4 AMR AF: 0.0775

Gnomad4 ASJ AF: 0.0516

Gnomad4 EAS AF: 0.0999

Gnomad4 SAS AF: 0.105

Gnomad4 FIN AF: 0.0160

Gnomad4 NFE AF: 0.0617

Gnomad4 OTH AF: 0.0932

Alfa AF: 0.0329 Hom.: 28

Bravo AF: 0.117

Asia WGS AF: 0.110 AC: 382 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.063
DANN	Benign	0.62
BranchPoint Hunter		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs73370824; hg19: chr21-46907338;