rs2838951

Positions:

• chr21-45509806-G-C
• chr21-45509806-G-A
• chr21-45509806-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001379500.1(COL18A1):​c.3495+205G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.627 in 151,126 control chromosomes in the GnomAD database, including 29,845 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.63 (29845 hom., cov: 35)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.47

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 21-45509806-G-C is Benign according to our data. Variant chr21-45509806-G-C is described in ClinVar as [Benign]. Clinvar id is 1238687.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.732 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.3495+205G>C		intron_variant		ENST00000651438.1	NP_001366429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.3495+205G>C		intron_variant			NM_001379500.1	ENSP00000498485

Frequencies

GnomAD3 genomes AF: 0.627 AC: 94647 AN: 151016 Hom.: 29823 Cov.: 35

Gnomad AFR AF: 0.739

Gnomad AMI AF: 0.496

Gnomad AMR AF: 0.628

Gnomad ASJ AF: 0.537

Gnomad EAS AF: 0.628

Gnomad SAS AF: 0.619

Gnomad FIN AF: 0.647

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.563

Gnomad OTH AF: 0.635

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.627 AC: 94708 AN: 151126 Hom.: 29845 Cov.: 35 AF XY: 0.630 AC XY: 46528 AN XY: 73876

Gnomad4 AFR AF: 0.739

Gnomad4 AMR AF: 0.627

Gnomad4 ASJ AF: 0.537

Gnomad4 EAS AF: 0.628

Gnomad4 SAS AF: 0.618

Gnomad4 FIN AF: 0.647

Gnomad4 NFE AF: 0.563

Gnomad4 OTH AF: 0.630

Alfa AF: 0.446 Hom.: 1142

Bravo AF: 0.624

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	-0.91
CADD	Benign	0.32
DANN	Benign	0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs2838951; hg19: chr21-46929720;