21-45495128-A-G

Variant names:

• chr21-45495128-A-G
• rs2236475
• ENST00000417954.5:c.*1207T>C

Variant summary

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

The ENST00000417954.5(SLC19A1):​c.*1207T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.273 in 641,592 control chromosomes in the GnomAD database, including 25,682 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 0.32 (8538 hom., cov: 34)
  • Exomes 𝑓: 0.26 (17144 hom.)
• Consequence: SLC19A1 ENST00000417954.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.700
• Publications: 15 publications found

Genes affected

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]

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]

COL18A1 Gene-Disease associations (from GenCC):

• Knobloch syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• Knobloch syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet
• hereditary glaucoma, primary closed-angle

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.464 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000417954.5. 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.2433+213A>G		intron	N/A	NP_001366429.1	P39060-2
	COL18A1	NM_130444.3		c.3678+213A>G		intron	N/A	NP_569711.2
	COL18A1	NM_030582.4		c.2973+213A>G		intron	N/A	NP_085059.2	A0AAG2UXZ5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC19A1	ENST00000417954.5	TSL:1	c.*1207T>C		3_prime_UTR	Exon 5 of 5	ENSP00000393988.1	H0Y4T2
	COL18A1	ENST00000651438.1	MANE Select	c.2433+213A>G		intron	N/A	ENSP00000498485.1	P39060-2
	COL18A1	ENST00000355480.10	TSL:1	c.2973+213A>G		intron	N/A	ENSP00000347665.5	P39060-1

Frequencies

GnomAD3 genomes AF: 0.316 AC: 48047 AN: 152002 Hom.: 8514 Cov.: 34

Gnomad AFR AF: 0.469

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.284

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.314

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.294

GnomAD4 exome AF: 0.259 AC: 126766 AN: 489472 Hom.: 17144 Cov.: 5 AF XY: 0.260 AC XY: 67230 AN XY: 258438

African (AFR) AF: 0.479 AC: 6650 AN: 13890

American (AMR) AF: 0.212 AC: 5513 AN: 26036

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 3957 AN: 15026

East Asian (EAS) AF: 0.197 AC: 6195 AN: 31444

South Asian (SAS) AF: 0.268 AC: 13559 AN: 50592

European-Finnish (FIN) AF: 0.288 AC: 8949 AN: 31050

Middle Eastern (MID) AF: 0.322 AC: 676 AN: 2100

European-Non Finnish (NFE) AF: 0.252 AC: 73706 AN: 291906

Other (OTH) AF: 0.276 AC: 7561 AN: 27428

GnomAD4 genome AF: 0.316 AC: 48116 AN: 152120 Hom.: 8538 Cov.: 34 AF XY: 0.317 AC XY: 23574 AN XY: 74354

African (AFR) AF: 0.470 AC: 19501 AN: 41506

American (AMR) AF: 0.242 AC: 3695 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 985 AN: 3470

East Asian (EAS) AF: 0.228 AC: 1173 AN: 5154

South Asian (SAS) AF: 0.262 AC: 1262 AN: 4824

European-Finnish (FIN) AF: 0.314 AC: 3319 AN: 10580

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.253 AC: 17205 AN: 67972

Other (OTH) AF: 0.294 AC: 623 AN: 2116

Alfa AF: 0.258 Hom.: 10695

Bravo AF: 0.318

Asia WGS AF: 0.251 AC: 876 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	4.9
DANN	Benign	0.58
PhyloP100		0.70
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: rs2236475; hg19: chr21-46915042; COSMIC: COSV60594768; COSMIC: COSV60594768;