chr21-45494523-GTCT-G

Variant names:

• chr21-45494523-GTCT-G
• rs762244775
• ENST00000417954.5:c.*1809_*1811delAGA

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The ENST00000417954.5(SLC19A1):​c.*1809_*1811delAGA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000241 in 1,613,300 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00023 (1 hom.)
• Consequence: SLC19A1 ENST00000417954.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.201
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 21-45494523-GTCT-G is Benign according to our data. Variant chr21-45494523-GTCT-G is described in ClinVar as Benign. ClinVar VariationId is 1169299.Status of the report is criteria_provided_single_submitter, 1 stars.

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.2353-17_2353-15delCTT		intron	N/A	NP_001366429.1	P39060-2
	COL18A1	NM_130444.3		c.3598-17_3598-15delCTT		intron	N/A	NP_569711.2
	COL18A1	NM_030582.4		c.2893-17_2893-15delCTT		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.*1809_*1811delAGA		3_prime_UTR	Exon 5 of 5	ENSP00000393988.1	H0Y4T2
	COL18A1	ENST00000651438.1	MANE Select	c.2353-17_2353-15delCTT		intron	N/A	ENSP00000498485.1	P39060-2
	COL18A1	ENST00000355480.10	TSL:1	c.2893-17_2893-15delCTT		intron	N/A	ENSP00000347665.5	P39060-1

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 48 AN: 152238 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000419 AC: 104 AN: 248276 AF XY: 0.000333

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000435

Gnomad ASJ exome AF: 0.00750

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000233 AC: 341 AN: 1461062 Hom.: 1 AF XY: 0.000226 AC XY: 164 AN XY: 726806

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000380 AC: 17 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00865 AC: 226 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52716

Middle Eastern (MID) AF: 0.000697 AC: 4 AN: 5738

European-Non Finnish (NFE) AF: 0.0000468 AC: 52 AN: 1111952

Other (OTH) AF: 0.000679 AC: 41 AN: 60372

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152238 Hom.: 0 Cov.: 34 AF XY: 0.000269 AC XY: 20 AN XY: 74376

African (AFR) AF: 0.0000724 AC: 3 AN: 41462

American (AMR) AF: 0.000131 AC: 2 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00979 AC: 34 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68038

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.00139 Hom.: 0

Bravo AF: 0.000340

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
PhyloP100		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs762244775; hg19: chr21-46914437;