rs397867048

chr21-45496602-AC-Achr21-45496602-ACC-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001379500.1(COL18A1):c.2577+37del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.441 in 978,970 control chromosomes in the GnomAD database, including 99,269 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (18617 hom., cov: 0)
  • Exomes 𝑓: 0.43 (80652 hom.)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.56

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 -16 ACMG points.

• BP6: Variant 21-45496602-AC-A is Benign according to our data. Variant chr21-45496602-AC-A is described in ClinVar as [Benign]. Clinvar id is 261902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.582 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL18A1	NM_001379500.1	c.2577+37del		intron_variant		ENST00000651438.1
COL18A1	NM_030582.4	c.3117+37del		intron_variant
COL18A1	NM_130444.3	c.3822+37del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL18A1	ENST00000651438.1	c.2577+37del		intron_variant			NM_001379500.1

Frequencies

GnomAD3 genomes AF: 0.488 AC: 74077 AN: 151798 Hom.: 18591 Cov.: 0

Gnomad AFR AF: 0.588

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.434

Gnomad ASJ AF: 0.463

Gnomad EAS AF: 0.377

Gnomad SAS AF: 0.415

Gnomad FIN AF: 0.538

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.447

Gnomad OTH AF: 0.488

GnomAD3 exomes AF: 0.448 AC: 109638 AN: 244798 Hom.: 25039 AF XY: 0.447 AC XY: 59954 AN XY: 134168

Gnomad AFR exome AF: 0.597

Gnomad AMR exome AF: 0.405

Gnomad ASJ exome AF: 0.442

Gnomad EAS exome AF: 0.393

Gnomad SAS exome AF: 0.415

Gnomad FIN exome AF: 0.518

Gnomad NFE exome AF: 0.446

Gnomad OTH exome AF: 0.455

GnomAD4 exome AF: 0.432 AC: 357651 AN: 827050 Hom.: 80652 Cov.: 0 AF XY: 0.434 AC XY: 189206 AN XY: 436380

Gnomad4 AFR exome AF: 0.590

Gnomad4 AMR exome AF: 0.409

Gnomad4 ASJ exome AF: 0.447

Gnomad4 EAS exome AF: 0.320

Gnomad4 SAS exome AF: 0.416

Gnomad4 FIN exome AF: 0.511

Gnomad4 NFE exome AF: 0.428

Gnomad4 OTH exome AF: 0.447

GnomAD4 genome AF: 0.488 AC: 74142 AN: 151920 Hom.: 18617 Cov.: 0 AF XY: 0.491 AC XY: 36488 AN XY: 74266

Gnomad4 AFR AF: 0.589

Gnomad4 AMR AF: 0.433

Gnomad4 ASJ AF: 0.463

Gnomad4 EAS AF: 0.377

Gnomad4 SAS AF: 0.416

Gnomad4 FIN AF: 0.538

Gnomad4 NFE AF: 0.447

Gnomad4 OTH AF: 0.487

Alfa AF: 0.465 Hom.: 3012

Bravo AF: 0.486

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Glaucoma, primary closed-angle Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 27, 2021

- -

Knobloch syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

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: rs397867048; hg19: chr21-46916516;