rs373823632

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The ENST00000651438.1(COL18A1):c.3087+8_3087+9delTC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0166 in 1,510,956 control chromosomes in the GnomAD database, including 341 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 50 hom., cov: 34)

Exomes 𝑓: 0.016 ( 291 hom. )

Consequence

COL18A1
ENST00000651438.1 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.246

Variant links:

Genes affected

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 links:

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]

SLC19A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0191 (2913/152308) while in subpopulation SAS AF = 0.0377 (182/4832). AF 95% confidence interval is 0.0332. There are 50 homozygotes in GnomAd4. There are 1542 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position FAILED quality control check.

BS2

High Homozygotes in GnomAd4 at 50 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL18A1	NM_001379500.1 link	c.3087+9_3087+10delCT		intron_variant	Intron 36 of 41	ENST00000651438.1	NP_001366429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1 link	c.3087+8_3087+9delTC		splice_region_variant, intron_variant	Intron 36 of 41		NM_001379500.1	ENSP00000498485.1		P39060-2

Frequencies

GnomAD3 genomes

AF:

0.0190

AC:

2899

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0191

Gnomad AMI

AF:

0.0242

Gnomad AMR

AF:

0.0121

Gnomad ASJ

AF:

0.0176

Gnomad EAS

AF:

0.00404

Gnomad SAS

AF:

0.0376

Gnomad FIN

AF:

0.0478

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0159

Gnomad OTH

AF:

0.0124

GnomAD2 exomes

AF:

0.0206

AC:

4013

AN:

195062

AF XY:

0.0223

show subpopulations

Gnomad AFR exome

AF:

0.0195

Gnomad AMR exome

AF:

0.0110

Gnomad ASJ exome

AF:

0.0194

Gnomad EAS exome

AF:

0.00436

Gnomad FIN exome

AF:

0.0425

Gnomad NFE exome

AF:

0.0165

Gnomad OTH exome

AF:

0.0245

GnomAD4 exome

AF:

0.0163

AC:

22193

AN:

1358648

Hom.:

291

AF XY:

0.0172

AC XY:

11677

AN XY:

677534

show subpopulations

Gnomad4 AFR exome

AF:

0.0208

AC:

661

AN:

31818

Gnomad4 AMR exome

AF:

0.0106

AC:

407

AN:

38470

Gnomad4 ASJ exome

AF:

0.0169

AC:

424

AN:

25154

Gnomad4 EAS exome

AF:

0.00171

AC:

AN:

38516

Gnomad4 SAS exome

AF:

0.0359

AC:

2917

AN:

81352

Gnomad4 FIN exome

AF:

0.0388

AC:

1890

AN:

48740

Gnomad4 NFE exome

AF:

0.0141

AC:

14604

AN:

1033568

Gnomad4 Remaining exome

AF:

0.0183

AC:

1043

AN:

56946

Heterozygous variant carriers

994

1988

2983

3977

4971

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

528

1056

1584

2112

2640

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0191

AC:

2913

AN:

152308

Hom.:

Cov.:

AF XY:

0.0207

AC XY:

1542

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.0194

AC:

0.019439

AN:

0.019439

Gnomad4 AMR

AF:

0.0121

AC:

0.0120836

AN:

0.0120836

Gnomad4 ASJ

AF:

0.0176

AC:

0.0175691

AN:

0.0175691

Gnomad4 EAS

AF:

0.00425

AC:

0.00424547

AN:

0.00424547

Gnomad4 SAS

AF:

0.0377

AC:

0.0376656

AN:

0.0376656

Gnomad4 FIN

AF:

0.0478

AC:

0.0478073

AN:

0.0478073

Gnomad4 NFE

AF:

0.0159

AC:

0.0159113

AN:

0.0159113

Gnomad4 OTH

AF:

0.0123

AC:

0.012299

AN:

0.012299

Heterozygous variant carriers

144

288

433

577

721

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0162

Hom.:

Bravo

AF:

0.0162

Asia WGS

AF:

0.0170

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

COL18A1: BS1, BS2; SLC19A1: BS1, BS2 -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over