rs12483553

Variant names:

• chr21-45506179-G-A
• rs12483553
• NM_001379500.1:c.3216+213G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001379500.1(COL18A1):​c.3216+213G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 651,166 control chromosomes in the GnomAD database, including 4,135 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1212 hom., cov: 35)
  • Exomes 𝑓: 0.10 (2923 hom.)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.58
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant 21-45506179-G-A is Benign according to our data. Variant chr21-45506179-G-A is described in ClinVar as Benign. ClinVar VariationId is 1232568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.168 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.3216+213G>A		intron	N/A	NP_001366429.1	P39060-2
	COL18A1	NM_130444.3		c.4461+213G>A		intron	N/A	NP_569711.2
	COL18A1	NM_030582.4		c.3756+213G>A		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.3216+213G>A		intron	N/A	ENSP00000498485.1	P39060-2
	COL18A1	ENST00000355480.10	TSL:1	c.3756+213G>A		intron	N/A	ENSP00000347665.5	P39060-1
	SLC19A1	ENST00000567670.5	TSL:1	c.1294-7567C>T		intron	N/A	ENSP00000457278.1	H3BTQ3

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18719 AN: 152202 Hom.: 1208 Cov.: 35

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.0857

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.0173

Gnomad SAS AF: 0.0678

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.133

GnomAD4 exome AF: 0.103 AC: 51233 AN: 498846 Hom.: 2923 Cov.: 6 AF XY: 0.101 AC XY: 26376 AN XY: 262314

African (AFR) AF: 0.136 AC: 1850 AN: 13606

American (AMR) AF: 0.178 AC: 4293 AN: 24148

Ashkenazi Jewish (ASJ) AF: 0.0970 AC: 1435 AN: 14794

East Asian (EAS) AF: 0.0106 AC: 309 AN: 29050

South Asian (SAS) AF: 0.0791 AC: 4020 AN: 50824

European-Finnish (FIN) AF: 0.128 AC: 3395 AN: 26572

Middle Eastern (MID) AF: 0.0906 AC: 184 AN: 2032

European-Non Finnish (NFE) AF: 0.106 AC: 32846 AN: 310906

Other (OTH) AF: 0.108 AC: 2901 AN: 26914

GnomAD4 genome AF: 0.123 AC: 18736 AN: 152320 Hom.: 1212 Cov.: 35 AF XY: 0.122 AC XY: 9107 AN XY: 74488

African (AFR) AF: 0.148 AC: 6147 AN: 41566

American (AMR) AF: 0.174 AC: 2663 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 355 AN: 3470

East Asian (EAS) AF: 0.0171 AC: 89 AN: 5194

South Asian (SAS) AF: 0.0666 AC: 322 AN: 4832

European-Finnish (FIN) AF: 0.129 AC: 1374 AN: 10616

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.109 AC: 7401 AN: 68018

Other (OTH) AF: 0.132 AC: 280 AN: 2114

Alfa AF: 0.113 Hom.: 1365

Bravo AF: 0.128

Asia WGS AF: 0.0480 AC: 167 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.51
DANN	Benign	0.41
PhyloP100		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12483553; hg19: chr21-46926093;