dbSNP rs2838952: COL18A1:p.Ile1227Ile (chr21-45510249-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001379500.1(COL18A1):c.3681C>T(p.Ile1227Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0319 in 1,604,708 control chromosomes in the GnomAD database, including 1,174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 88 hom., cov: 34)

Exomes 𝑓: 0.032 ( 1086 hom. )

Consequence

COL18A1
NM_001379500.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -3.73

Publications

5 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.086).

BP6

Variant 21-45510249-C-T is Benign according to our data. Variant chr21-45510249-C-T is described in ClinVar as Benign. ClinVar VariationId is 522315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.73 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0706 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	HGVSp	Effect	Exon Rank	Protein	UniProt
COL18A1	NM_001379500.1	MANE Select	c.3681C>T	p.Ile1227Ile	synonymous	Exon 40 of 42	NP_001366429.1	P39060-2
COL18A1	NM_130444.3		c.4926C>T	p.Ile1642Ile	synonymous	Exon 39 of 41	NP_569711.2
COL18A1	NM_030582.4		c.4221C>T	p.Ile1407Ile	synonymous	Exon 39 of 41	NP_085059.2	A0AAG2UXZ5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL18A1	ENST00000651438.1	MANE Select	c.3681C>T	p.Ile1227Ile	synonymous	Exon 40 of 42	ENSP00000498485.1	P39060-2
COL18A1	ENST00000355480.10	TSL:1	c.4221C>T	p.Ile1407Ile	synonymous	Exon 39 of 41	ENSP00000347665.5	P39060-1
SLC19A1	ENST00000567670.5	TSL:1	c.1294-11637G>A		intron	N/A	ENSP00000457278.1	H3BTQ3

Frequencies

GnomAD3 genomes

AF:

0.0267

AC:

4059

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00767

Gnomad AMI

AF:

0.0702

Gnomad AMR

AF:

0.0736

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0170

Gnomad FIN

AF:

0.0244

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0314

Gnomad OTH

AF:

0.0249

GnomAD2 exomes

AF:

0.0403

AC:

9068

AN:

225060

AF XY:

0.0353

show subpopulations

Gnomad AFR exome

AF:

0.00648

Gnomad AMR exome

AF:

0.142

Gnomad ASJ exome

AF:

0.00406

Gnomad EAS exome

AF:

0.000238

Gnomad FIN exome

AF:

0.0274

Gnomad NFE exome

AF:

0.0304

Gnomad OTH exome

AF:

0.0294

GnomAD4 exome

AF:

0.0324

AC:

47108

AN:

1452388

Hom.:

1086

Cov.:

AF XY:

0.0314

AC XY:

22682

AN XY:

722064

show subpopulations

African (AFR)

AF:

0.00521

AC:

173

AN:

33212

American (AMR)

AF:

0.130

AC:

5665

AN:

43726

Ashkenazi Jewish (ASJ)

AF:

0.00501

AC:

130

AN:

25950

East Asian (EAS)

AF:

0.000205

AC:

AN:

39104

South Asian (SAS)

AF:

0.0202

AC:

1714

AN:

84838

European-Finnish (FIN)

AF:

0.0275

AC:

1414

AN:

51452

Middle Eastern (MID)

AF:

0.0134

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0329

AC:

36442

AN:

1108364

Other (OTH)

AF:

0.0248

AC:

1485

AN:

59984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

2621

5242

7862

10483

13104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1434

2868

4302

5736

7170

<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:

0.0267

AC:

4071

AN:

152320

Hom.:

Cov.:

AF XY:

0.0271

AC XY:

2015

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00765

AC:

318

AN:

41574

American (AMR)

AF:

0.0742

AC:

1135

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00605

AC:

AN:

3470

East Asian (EAS)

AF:

0.000578

AC:

AN:

5186

South Asian (SAS)

AF:

0.0174

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0244

AC:

259

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0314

AC:

2135

AN:

68012

Other (OTH)

AF:

0.0246

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

207

414

620

827

1034

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<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:

0.0308

Hom.:

244

Bravo

AF:

0.0317

Asia WGS

AF:

0.0100

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Knobloch syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

2.6

(source)

DANN

Benign

0.94

PhyloP100

-3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=95/5

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