chr21-45493697-T-C

Variant names:

• chr21-45493697-T-C
• rs73228774
• ENST00000417954.5:c.*2638A>G

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.*2638A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 757,172 control chromosomes in the GnomAD database, including 12,531 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2243 hom., cov: 34)
  • Exomes 𝑓: 0.18 (10288 hom.)
• Consequence: SLC19A1 ENST00000417954.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.21
• Publications: 3 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=-1.0).
• BP6: Variant 21-45493697-T-C is Benign according to our data. Variant chr21-45493697-T-C is described in ClinVar as Benign. ClinVar VariationId is 1235277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.195 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.2352+122T>C		intron	N/A	NP_001366429.1	P39060-2
	COL18A1	NM_130444.3		c.3597+122T>C		intron	N/A	NP_569711.2
	COL18A1	NM_030582.4		c.2892+122T>C		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.*2638A>G		3_prime_UTR	Exon 5 of 5	ENSP00000393988.1	H0Y4T2
	COL18A1	ENST00000651438.1	MANE Select	c.2352+122T>C		intron	N/A	ENSP00000498485.1	P39060-2
	COL18A1	ENST00000355480.10	TSL:1	c.2892+122T>C		intron	N/A	ENSP00000347665.5	P39060-1

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25566 AN: 152064 Hom.: 2244 Cov.: 34

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.201

Gnomad ASJ AF: 0.232

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.166

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.195

GnomAD4 exome AF: 0.180 AC: 109102 AN: 604990 Hom.: 10288 Cov.: 8 AF XY: 0.180 AC XY: 57032 AN XY: 317530

African (AFR) AF: 0.114 AC: 1829 AN: 16040

American (AMR) AF: 0.207 AC: 5857 AN: 28268

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 3989 AN: 16680

East Asian (EAS) AF: 0.119 AC: 3812 AN: 31926

South Asian (SAS) AF: 0.153 AC: 8474 AN: 55264

European-Finnish (FIN) AF: 0.154 AC: 5715 AN: 37182

Middle Eastern (MID) AF: 0.209 AC: 510 AN: 2444

European-Non Finnish (NFE) AF: 0.190 AC: 73202 AN: 385924

Other (OTH) AF: 0.183 AC: 5714 AN: 31262

GnomAD4 genome AF: 0.168 AC: 25561 AN: 152182 Hom.: 2243 Cov.: 34 AF XY: 0.168 AC XY: 12519 AN XY: 74422

African (AFR) AF: 0.113 AC: 4703 AN: 41542

American (AMR) AF: 0.201 AC: 3073 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.232 AC: 805 AN: 3470

East Asian (EAS) AF: 0.148 AC: 764 AN: 5158

South Asian (SAS) AF: 0.158 AC: 761 AN: 4828

European-Finnish (FIN) AF: 0.166 AC: 1758 AN: 10618

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

European-Non Finnish (NFE) AF: 0.193 AC: 13139 AN: 67958

Other (OTH) AF: 0.194 AC: 409 AN: 2112

Alfa AF: 0.177 Hom.: 269

Bravo AF: 0.169

Asia WGS AF: 0.155 AC: 539 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	-1.0
CADD	Benign	1.6
DANN	Benign	0.74
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs73228774; hg19: chr21-46913611;