rs7278425

Variant names:

• chr21-45506637-C-T
• rs7278425
• NM_001379500.1:c.3216+671C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001379500.1(COL18A1):​c.3216+671C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 169,318 control chromosomes in the GnomAD database, including 2,968 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.19 (2736 hom., cov: 33)
  • Exomes 𝑓: 0.15 (232 hom.)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.07
• Publications: 12 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.06).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.214 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+671C>T		intron	N/A	NP_001366429.1	P39060-2
	COL18A1	NM_130444.3		c.4461+671C>T		intron	N/A	NP_569711.2
	COL18A1	NM_030582.4		c.3756+671C>T		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+671C>T		intron	N/A	ENSP00000498485.1	P39060-2
	COL18A1	ENST00000355480.10	TSL:1	c.3756+671C>T		intron	N/A	ENSP00000347665.5	P39060-1
	SLC19A1	ENST00000567670.5	TSL:1	c.1294-8025G>A		intron	N/A	ENSP00000457278.1	H3BTQ3

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28457 AN: 152048 Hom.: 2730 Cov.: 33

Gnomad AFR AF: 0.218

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.209

Gnomad ASJ AF: 0.170

Gnomad EAS AF: 0.0553

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.214

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.188

GnomAD4 exome AF: 0.150 AC: 2568 AN: 17152 Hom.: 232 Cov.: 0 AF XY: 0.152 AC XY: 1377 AN XY: 9088

African (AFR) AF: 0.216 AC: 74 AN: 342

American (AMR) AF: 0.190 AC: 591 AN: 3116

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 27 AN: 160

East Asian (EAS) AF: 0.0461 AC: 63 AN: 1368

South Asian (SAS) AF: 0.141 AC: 356 AN: 2518

European-Finnish (FIN) AF: 0.158 AC: 48 AN: 304

Middle Eastern (MID) AF: 0.233 AC: 7 AN: 30

European-Non Finnish (NFE) AF: 0.151 AC: 1302 AN: 8606

Other (OTH) AF: 0.141 AC: 100 AN: 708

GnomAD4 genome AF: 0.187 AC: 28482 AN: 152166 Hom.: 2736 Cov.: 33 AF XY: 0.187 AC XY: 13911 AN XY: 74416

African (AFR) AF: 0.218 AC: 9056 AN: 41506

American (AMR) AF: 0.209 AC: 3197 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 591 AN: 3472

East Asian (EAS) AF: 0.0552 AC: 286 AN: 5180

South Asian (SAS) AF: 0.148 AC: 713 AN: 4832

European-Finnish (FIN) AF: 0.214 AC: 2265 AN: 10598

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.174 AC: 11809 AN: 67960

Other (OTH) AF: 0.187 AC: 395 AN: 2110

Alfa AF: 0.177 Hom.: 8873

Bravo AF: 0.187

Asia WGS AF: 0.110 AC: 383 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.71
DANN	Benign	0.57
PhyloP100		-3.1
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs7278425;

hg19: chr21-46926551;