21-45506088-C-G

Position:

• chr21-45506088-C-G

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.3216+122C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,472,470 control chromosomes in the GnomAD database, including 12,627 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1542 hom., cov: 34)
  • Exomes 𝑓: 0.13 (11085 hom.)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.08

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]

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 21-45506088-C-G is Benign according to our data. Variant chr21-45506088-C-G is described in ClinVar as [Benign]. Clinvar id is 1222843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.3216+122C>G		intron_variant		ENST00000651438.1	NP_001366429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.3216+122C>G		intron_variant			NM_001379500.1	ENSP00000498485

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21232 AN: 152200 Hom.: 1538 Cov.: 34

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.0173

Gnomad SAS AF: 0.0810

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.151

GnomAD4 exome AF: 0.127 AC: 167280 AN: 1320152 Hom.: 11085 Cov.: 19 AF XY: 0.125 AC XY: 82733 AN XY: 660306

Gnomad4 AFR exome AF: 0.148

Gnomad4 AMR exome AF: 0.186

Gnomad4 ASJ exome AF: 0.126

Gnomad4 EAS exome AF: 0.0109

Gnomad4 SAS exome AF: 0.0885

Gnomad4 FIN exome AF: 0.161

Gnomad4 NFE exome AF: 0.130

Gnomad4 OTH exome AF: 0.126

GnomAD4 genome AF: 0.140 AC: 21250 AN: 152318 Hom.: 1542 Cov.: 34 AF XY: 0.139 AC XY: 10341 AN XY: 74476

Gnomad4 AFR AF: 0.151

Gnomad4 AMR AF: 0.187

Gnomad4 ASJ AF: 0.128

Gnomad4 EAS AF: 0.0172

Gnomad4 SAS AF: 0.0801

Gnomad4 FIN AF: 0.162

Gnomad4 NFE AF: 0.133

Gnomad4 OTH AF: 0.150

Alfa AF: 0.144 Hom.: 173

Bravo AF: 0.141

Asia WGS AF: 0.0580 AC: 201 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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.96
DANN	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs10483080; hg19: chr21-46926002;