NM_001379500.1:c.3694-32C>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001379500.1(COL18A1):c.3694-32C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.46 ( 12704 hom., cov: 17)

Exomes 𝑓: 0.40 ( 77414 hom. )

Consequence

COL18A1
NM_001379500.1 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -2.97

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

combined immunodeficiency
Inheritance: AR Classification: MODERATE Submitted by: PanelApp Australia
immunodeficiency 114, folate-responsive
Inheritance: AR Classification: LIMITED Submitted by: ClinGen
megaloblastic anemia, folate-responsive
Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

SLC19A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 21-45511079-C-A is Benign according to our data. Variant chr21-45511079-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.542 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379500.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
COL18A1	NM_001379500.1	MANE Select	c.3694-32C>A	intron	N/A	NP_001366429.1	P39060-2
COL18A1	NM_130444.3		c.4939-32C>A	intron	N/A	NP_569711.2
COL18A1	NM_030582.4		c.4234-32C>A	intron	N/A	NP_085059.2	A0AAG2UXZ5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
COL18A1	ENST00000651438.1	MANE Select	c.3694-32C>A	intron	N/A	ENSP00000498485.1	P39060-2
COL18A1	ENST00000355480.10	TSL:1	c.4234-32C>A	intron	N/A	ENSP00000347665.5	P39060-1
SLC19A1	ENST00000567670.5	TSL:1	c.1294-12467G>T	intron	N/A	ENSP00000457278.1	H3BTQ3

Frequencies

GnomAD3 genomes

AF:

0.457

AC:

56287

AN:

123296

Hom.:

12701

Cov.:

show subpopulations

Gnomad AFR

AF:

0.510

Gnomad AMI

AF:

0.376

Gnomad AMR

AF:

0.435

Gnomad ASJ

AF:

0.404

Gnomad EAS

AF:

0.560

Gnomad SAS

AF:

0.497

Gnomad FIN

AF:

0.451

Gnomad MID

AF:

0.493

Gnomad NFE

AF:

0.430

Gnomad OTH

AF:

0.477

GnomAD2 exomes

AF:

0.452

AC:

64912

AN:

143558

AF XY:

0.453

show subpopulations

Gnomad AFR exome

AF:

0.511

Gnomad AMR exome

AF:

0.441

Gnomad ASJ exome

AF:

0.396

Gnomad EAS exome

AF:

0.571

Gnomad FIN exome

AF:

0.442

Gnomad NFE exome

AF:

0.421

Gnomad OTH exome

AF:

0.466

GnomAD4 exome

AF:

0.399

AC:

360959

AN:

905792

Hom.:

77414

Cov.:

AF XY:

0.404

AC XY:

188013

AN XY:

465722

show subpopulations

African (AFR)

AF:

0.432

AC:

9146

AN:

21194

American (AMR)

AF:

0.427

AC:

14834

AN:

34748

Ashkenazi Jewish (ASJ)

AF:

0.391

AC:

8598

AN:

21980

East Asian (EAS)

AF:

0.581

AC:

18884

AN:

32512

South Asian (SAS)

AF:

0.475

AC:

32881

AN:

69292

European-Finnish (FIN)

AF:

0.453

AC:

19825

AN:

43774

Middle Eastern (MID)

AF:

0.483

AC:

2232

AN:

4618

European-Non Finnish (NFE)

AF:

0.373

AC:

237502

AN:

636446

Other (OTH)

AF:

0.414

AC:

17057

AN:

41228

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

9072

18144

27217

36289

45361

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5248

10496

15744

20992

26240

<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:

0.456

AC:

56295

AN:

123364

Hom.:

12704

Cov.:

AF XY:

0.458

AC XY:

26968

AN XY:

58906

show subpopulations

African (AFR)

AF:

0.510

AC:

14763

AN:

28964

American (AMR)

AF:

0.434

AC:

5300

AN:

12216

Ashkenazi Jewish (ASJ)

AF:

0.404

AC:

1286

AN:

3186

East Asian (EAS)

AF:

0.561

AC:

2307

AN:

4112

South Asian (SAS)

AF:

0.497

AC:

1867

AN:

3758

European-Finnish (FIN)

AF:

0.451

AC:

3189

AN:

7066

Middle Eastern (MID)

AF:

0.500

AC:

127

AN:

254

European-Non Finnish (NFE)

AF:

0.430

AC:

26337

AN:

61274

Other (OTH)

AF:

0.472

AC:

820

AN:

1738

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.524

Heterozygous variant carriers

1335

2670

4005

5340

6675

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

510

1020

1530

2040

2550

<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:

0.416

Hom.:

2034

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.47

(source)

DANN

Benign

0.23

PhyloP100

-3.0

BranchPoint Hunter

1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over