rs56335679

chr21-45511078-A-Cchr21-45511078-A-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.3694-33A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.427 in 958,950 control chromosomes in the GnomAD database, including 88,341 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (12714 hom., cov: 17)
  • Exomes 𝑓: 0.42 (75627 hom.)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.82

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=-0.92).
• BP6: Variant 21-45511078-A-C is Benign according to our data. Variant chr21-45511078-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 261917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL18A1	NM_001379500.1	c.3694-33A>C		intron_variant		ENST00000651438.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL18A1	ENST00000651438.1	c.3694-33A>C		intron_variant			NM_001379500.1

Frequencies

GnomAD3 genomes AF: 0.478 AC: 56155 AN: 117524 Hom.: 12711 Cov.: 17

Gnomad AFR AF: 0.525

Gnomad AMI AF: 0.401

Gnomad AMR AF: 0.472

Gnomad ASJ AF: 0.420

Gnomad EAS AF: 0.594

Gnomad SAS AF: 0.536

Gnomad FIN AF: 0.500

Gnomad MID AF: 0.508

Gnomad NFE AF: 0.446

Gnomad OTH AF: 0.496

GnomAD3 exomes AF: 0.452 AC: 64732 AN: 143278 Hom.: 14686 AF XY: 0.453 AC XY: 34724 AN XY: 76670

Gnomad AFR exome AF: 0.509

Gnomad AMR exome AF: 0.441

Gnomad ASJ exome AF: 0.395

Gnomad EAS exome AF: 0.571

Gnomad SAS exome AF: 0.488

Gnomad FIN exome AF: 0.442

Gnomad NFE exome AF: 0.421

Gnomad OTH exome AF: 0.465

GnomAD4 exome AF: 0.420 AC: 353659 AN: 841384 Hom.: 75627 Cov.: 12 AF XY: 0.425 AC XY: 184547 AN XY: 433862

Gnomad4 AFR exome AF: 0.443

Gnomad4 AMR exome AF: 0.439

Gnomad4 ASJ exome AF: 0.427

Gnomad4 EAS exome AF: 0.628

Gnomad4 SAS exome AF: 0.477

Gnomad4 FIN exome AF: 0.482

Gnomad4 NFE exome AF: 0.395

Gnomad4 OTH exome AF: 0.444

GnomAD4 genome AF: 0.478 AC: 56163 AN: 117566 Hom.: 12714 Cov.: 17 AF XY: 0.483 AC XY: 26897 AN XY: 55650

Gnomad4 AFR AF: 0.525

Gnomad4 AMR AF: 0.471

Gnomad4 ASJ AF: 0.420

Gnomad4 EAS AF: 0.595

Gnomad4 SAS AF: 0.535

Gnomad4 FIN AF: 0.500

Gnomad4 NFE AF: 0.446

Gnomad4 OTH AF: 0.493

Alfa AF: 0.424 Hom.: 2244

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

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	-0.92
Cadd	Benign	0.14
Dann	Benign	0.13

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: rs56335679; hg19: chr21-46930992; COSMIC: COSV60589788; COSMIC: COSV60589788;