chr21-45506383-C-T

Variant names:

• chr21-45506383-C-T
• rs2838950
• NM_001379500.1:c.3216+417C>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+417C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 336,074 control chromosomes in the GnomAD database, including 17,242 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 0.31 (8198 hom., cov: 34)
  • Exomes 𝑓: 0.29 (9044 hom.)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.722
• Publications: 7 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=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.544 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+417C>T		intron	N/A	NP_001366429.1	P39060-2
	COL18A1	NM_130444.3		c.4461+417C>T		intron	N/A	NP_569711.2
	COL18A1	NM_030582.4		c.3756+417C>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+417C>T		intron	N/A	ENSP00000498485.1	P39060-2
	COL18A1	ENST00000355480.10	TSL:1	c.3756+417C>T		intron	N/A	ENSP00000347665.5	P39060-1
	SLC19A1	ENST00000567670.5	TSL:1	c.1294-7771G>A		intron	N/A	ENSP00000457278.1	H3BTQ3

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47657 AN: 152072 Hom.: 8193 Cov.: 34

Gnomad AFR AF: 0.420

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.367

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.561

Gnomad SAS AF: 0.429

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.229

Gnomad OTH AF: 0.334

GnomAD4 exome AF: 0.292 AC: 53603 AN: 183884 Hom.: 9044 Cov.: 0 AF XY: 0.304 AC XY: 30367 AN XY: 99774

African (AFR) AF: 0.424 AC: 2159 AN: 5092

American (AMR) AF: 0.415 AC: 3731 AN: 8986

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 1156 AN: 4300

East Asian (EAS) AF: 0.575 AC: 4359 AN: 7586

South Asian (SAS) AF: 0.402 AC: 14773 AN: 36722

European-Finnish (FIN) AF: 0.206 AC: 1700 AN: 8256

Middle Eastern (MID) AF: 0.345 AC: 218 AN: 632

European-Non Finnish (NFE) AF: 0.222 AC: 22979 AN: 103452

Other (OTH) AF: 0.285 AC: 2528 AN: 8858

GnomAD4 genome AF: 0.313 AC: 47684 AN: 152190 Hom.: 8198 Cov.: 34 AF XY: 0.316 AC XY: 23533 AN XY: 74400

African (AFR) AF: 0.420 AC: 17432 AN: 41540

American (AMR) AF: 0.367 AC: 5611 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 998 AN: 3470

East Asian (EAS) AF: 0.561 AC: 2897 AN: 5164

South Asian (SAS) AF: 0.428 AC: 2065 AN: 4826

European-Finnish (FIN) AF: 0.196 AC: 2084 AN: 10606

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.229 AC: 15571 AN: 67970

Other (OTH) AF: 0.331 AC: 698 AN: 2108

Alfa AF: 0.243 Hom.: 3558

Bravo AF: 0.332

Asia WGS AF: 0.482 AC: 1677 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.65
DANN	Benign	0.60
PhyloP100		-0.72
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: rs2838950; hg19: chr21-46926297;