21-45494348-C-T

Position:

• chr21-45494348-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.2353-197C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 713,740 control chromosomes in the GnomAD database, including 5,977 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1464 hom., cov: 33)
  • Exomes 𝑓: 0.12 (4513 hom.)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.24

Genes affected

SLC19A1 (HGNC:10937): (solute carrier family 19 member 1) The membrane protein encoded by this gene is a transporter of folate and is involved in the regulation of intracellular concentrations of folate. Three transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2011]

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]

COL18A1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 21-45494348-C-T is Benign according to our data. Variant chr21-45494348-C-T is described in ClinVar as [Benign]. Clinvar id is 1248480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.2353-197C>T		intron_variant		ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3	c.3598-197C>T		intron_variant			NP_569711.2
COL18A1	NM_030582.4	c.2893-197C>T		intron_variant			NP_085059.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.2353-197C>T		intron_variant			NM_001379500.1	ENSP00000498485.1

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20350 AN: 151930 Hom.: 1463 Cov.: 33

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.0983

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.0153

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.173

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.117

GnomAD4 exome AF: 0.119 AC: 67122 AN: 561692 Hom.: 4513 Cov.: 7 AF XY: 0.122 AC XY: 36359 AN XY: 298080

Gnomad4 AFR exome AF: 0.172

Gnomad4 AMR exome AF: 0.0767

Gnomad4 ASJ exome AF: 0.107

Gnomad4 EAS exome AF: 0.0141

Gnomad4 SAS exome AF: 0.152

Gnomad4 FIN exome AF: 0.151

Gnomad4 NFE exome AF: 0.123

Gnomad4 OTH exome AF: 0.117

GnomAD4 genome AF: 0.134 AC: 20370 AN: 152048 Hom.: 1464 Cov.: 33 AF XY: 0.134 AC XY: 9977 AN XY: 74314

Gnomad4 AFR AF: 0.168

Gnomad4 AMR AF: 0.0978

Gnomad4 ASJ AF: 0.106

Gnomad4 EAS AF: 0.0155

Gnomad4 SAS AF: 0.147

Gnomad4 FIN AF: 0.173

Gnomad4 NFE AF: 0.126

Gnomad4 OTH AF: 0.116

Alfa AF: 0.130 Hom.: 150

Bravo AF: 0.131

Asia WGS AF: 0.0830 AC: 292 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.89
DANN	Benign	0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs71324428; hg19: chr21-46914262; COSMIC: COSV60591907; COSMIC: COSV60591907;