rs749627

Variant names:

• chr21-45493603-A-G
• rs749627
• ENST00000417954.5:c.*2732T>C

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.*2732T>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 0.433 in 1,526,298 control chromosomes in the GnomAD database, including 145,577 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (19529 hom., cov: 35)
  • Exomes 𝑓: 0.43 (126048 hom.)
• Consequence: SLC19A1 ENST00000417954.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.28
• Publications: 9 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• 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=-0.96).
• BP6: Variant 21-45493603-A-G is Benign according to our data. Variant chr21-45493603-A-G is described in ClinVar as Benign. ClinVar VariationId is 261901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.654 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.2352+28A>G		intron_variant	Intron 26 of 41	ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3	c.3597+28A>G		intron_variant	Intron 25 of 40		NP_569711.2
COL18A1	NM_030582.4	c.2892+28A>G		intron_variant	Intron 25 of 40		NP_085059.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.2352+28A>G		intron_variant	Intron 26 of 41		NM_001379500.1	ENSP00000498485.1

Frequencies

GnomAD3 genomes AF: 0.494 AC: 75028 AN: 152016 Hom.: 19502 Cov.: 35

Gnomad AFR AF: 0.660

Gnomad AMI AF: 0.380

Gnomad AMR AF: 0.437

Gnomad ASJ AF: 0.509

Gnomad EAS AF: 0.472

Gnomad SAS AF: 0.456

Gnomad FIN AF: 0.452

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.416

Gnomad OTH AF: 0.489

GnomAD2 exomes AF: 0.444 AC: 66231 AN: 149326 AF XY: 0.442

Gnomad AFR exome AF: 0.661

Gnomad AMR exome AF: 0.412

Gnomad ASJ exome AF: 0.493

Gnomad EAS exome AF: 0.482

Gnomad FIN exome AF: 0.432

Gnomad NFE exome AF: 0.417

Gnomad OTH exome AF: 0.445

GnomAD4 exome AF: 0.426 AC: 585308 AN: 1374162 Hom.: 126048 Cov.: 26 AF XY: 0.426 AC XY: 289499 AN XY: 679146

African (AFR) AF: 0.681 AC: 21228 AN: 31176

American (AMR) AF: 0.418 AC: 14887 AN: 35656

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 12510 AN: 25026

East Asian (EAS) AF: 0.458 AC: 16305 AN: 35598

South Asian (SAS) AF: 0.447 AC: 35203 AN: 78682

European-Finnish (FIN) AF: 0.418 AC: 20002 AN: 47838

Middle Eastern (MID) AF: 0.494 AC: 2362 AN: 4784

European-Non Finnish (NFE) AF: 0.413 AC: 437303 AN: 1058284

Other (OTH) AF: 0.447 AC: 25508 AN: 57118

GnomAD4 genome AF: 0.494 AC: 75100 AN: 152136 Hom.: 19529 Cov.: 35 AF XY: 0.495 AC XY: 36833 AN XY: 74374

African (AFR) AF: 0.661 AC: 27406 AN: 41492

American (AMR) AF: 0.436 AC: 6674 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 1767 AN: 3470

East Asian (EAS) AF: 0.472 AC: 2439 AN: 5164

South Asian (SAS) AF: 0.456 AC: 2202 AN: 4830

European-Finnish (FIN) AF: 0.452 AC: 4793 AN: 10602

Middle Eastern (MID) AF: 0.469 AC: 138 AN: 294

European-Non Finnish (NFE) AF: 0.416 AC: 28303 AN: 67960

Other (OTH) AF: 0.489 AC: 1032 AN: 2112

Alfa AF: 0.457 Hom.: 3008

Bravo AF: 0.502

Asia WGS AF: 0.466 AC: 1624 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

May 10, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.1
DANN	Benign	0.68
PhyloP100		-2.3
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: rs749627; hg19: chr21-46913517; COSMIC: COSV107421616; COSMIC: COSV107421616;