rs60331963

Variant names:

• chr21-45494347-G-A
• rs60331963
• ENST00000417954.5:c.*1988C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-45494347-G-A
• chr21-45494347-G-T

Variant summary

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

The ENST00000417954.5(SLC19A1):​c.*1988C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 693,572 control chromosomes in the GnomAD database, including 11,317 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2206 hom., cov: 33)
  • Exomes 𝑓: 0.18 (9111 hom.)
• Consequence: SLC19A1 ENST00000417954.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.13
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 21-45494347-G-A is Benign according to our data. Variant chr21-45494347-G-A is described in ClinVar as Benign. ClinVar VariationId is 1245923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.196 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.2353-198G>A		intron	N/A	NP_001366429.1	P39060-2
	COL18A1	NM_130444.3		c.3598-198G>A		intron	N/A	NP_569711.2
	COL18A1	NM_030582.4		c.2893-198G>A		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.*1988C>T		3_prime_UTR	Exon 5 of 5	ENSP00000393988.1	H0Y4T2
	COL18A1	ENST00000651438.1	MANE Select	c.2353-198G>A		intron	N/A	ENSP00000498485.1	P39060-2
	COL18A1	ENST00000355480.10	TSL:1	c.2893-198G>A		intron	N/A	ENSP00000347665.5	P39060-1

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25213 AN: 150838 Hom.: 2208 Cov.: 33

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.0958

Gnomad AMR AF: 0.202

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.166

Gnomad MID AF: 0.188

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.192

GnomAD4 exome AF: 0.180 AC: 97845 AN: 542624 Hom.: 9111 Cov.: 7 AF XY: 0.179 AC XY: 51609 AN XY: 288306

African (AFR) AF: 0.110 AC: 1609 AN: 14584

American (AMR) AF: 0.210 AC: 6078 AN: 28936

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 3835 AN: 16470

East Asian (EAS) AF: 0.126 AC: 3769 AN: 29952

South Asian (SAS) AF: 0.152 AC: 8457 AN: 55464

European-Finnish (FIN) AF: 0.155 AC: 4867 AN: 31398

Middle Eastern (MID) AF: 0.213 AC: 484 AN: 2272

European-Non Finnish (NFE) AF: 0.190 AC: 63374 AN: 334252

Other (OTH) AF: 0.183 AC: 5372 AN: 29296

GnomAD4 genome AF: 0.167 AC: 25206 AN: 150948 Hom.: 2206 Cov.: 33 AF XY: 0.167 AC XY: 12335 AN XY: 73766

African (AFR) AF: 0.110 AC: 4501 AN: 40892

American (AMR) AF: 0.202 AC: 3067 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 768 AN: 3466

East Asian (EAS) AF: 0.148 AC: 750 AN: 5054

South Asian (SAS) AF: 0.160 AC: 760 AN: 4760

European-Finnish (FIN) AF: 0.166 AC: 1734 AN: 10440

Middle Eastern (MID) AF: 0.199 AC: 58 AN: 292

European-Non Finnish (NFE) AF: 0.193 AC: 13079 AN: 67820

Other (OTH) AF: 0.191 AC: 402 AN: 2102

Alfa AF: 0.172 Hom.: 269

Bravo AF: 0.167

Asia WGS AF: 0.153 AC: 534 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	-0.92
CADD	Benign	1.0
DANN	Benign	0.49
PhyloP100		-2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs60331963; hg19: chr21-46914261;