21-45509806-G-C

Variant names:

• chr21-45509806-G-C
• rs2838951
• NM_001379500.1:c.3495+205G>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 13 publications found

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]

SLC19A1 Gene-Disease associations (from GenCC):

• combined immunodeficiency

  Inheritance: AR Classification: MODERATE Submitted by: PanelApp Australia
• immunodeficiency 114, folate-responsive

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• megaloblastic anemia, folate-responsive

  Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379500.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	NM_001379500.1	MANE Select	c.3495+205G>C		intron	N/A	NP_001366429.1	P39060-2
	COL18A1	NM_130444.3		c.4740+205G>C		intron	N/A	NP_569711.2
	COL18A1	NM_030582.4		c.4035+205G>C		intron	N/A	NP_085059.2	A0AAG2UXZ5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.3495+205G>C		intron	N/A	ENSP00000498485.1	P39060-2
	COL18A1	ENST00000355480.10	TSL:1	c.4035+205G>C		intron	N/A	ENSP00000347665.5	P39060-1
	SLC19A1	ENST00000567670.5	TSL:1	c.1294-11194C>G		intron	N/A	ENSP00000457278.1	H3BTQ3

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

African (AFR) AF: 0.739 AC: 29998 AN: 40596

American (AMR) AF: 0.627 AC: 9574 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.537 AC: 1856 AN: 3458

East Asian (EAS) AF: 0.628 AC: 3232 AN: 5146

South Asian (SAS) AF: 0.618 AC: 2988 AN: 4832

European-Finnish (FIN) AF: 0.647 AC: 6861 AN: 10608

Middle Eastern (MID) AF: 0.646 AC: 190 AN: 294

European-Non Finnish (NFE) AF: 0.563 AC: 38243 AN: 67924

Other (OTH) AF: 0.630 AC: 1315 AN: 2088

Alfa AF: 0.446 Hom.: 1142

Bravo AF: 0.624

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.32
DANN	Benign	0.38
PhyloP100		-3.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2838951; hg19: chr21-46929720;