NM_001379500.1:c.3610G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001379500.1(COL18A1):c.3610G>A(p.Ala1204Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0158 in 1,597,036 control chromosomes in the GnomAD database, including 248 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1204G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.010 ( 18 hom., cov: 34)

Exomes 𝑓: 0.016 ( 230 hom. )

Consequence

COL18A1
NM_001379500.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 9.68

Publications

15 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 -16 ACMG points.

BP6

Variant 21-45510178-G-A is Benign according to our data. Variant chr21-45510178-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0101 (1539/152288) while in subpopulation SAS AF = 0.0209 (101/4826). AF 95% confidence interval is 0.0176. There are 18 homozygotes in GnomAd4. There are 701 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 18 AD,AR gene

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.3610G>A	p.Ala1204Thr	missense	Exon 40 of 42	NP_001366429.1	P39060-2
COL18A1	NM_130444.3		c.4855G>A	p.Ala1619Thr	missense	Exon 39 of 41	NP_569711.2
COL18A1	NM_030582.4		c.4150G>A	p.Ala1384Thr	missense	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.3610G>A	p.Ala1204Thr	missense	Exon 40 of 42	ENSP00000498485.1	P39060-2
COL18A1	ENST00000355480.10	TSL:1	c.4150G>A	p.Ala1384Thr	missense	Exon 39 of 41	ENSP00000347665.5	P39060-1
SLC19A1	ENST00000567670.5	TSL:1	c.1294-11566C>T		intron	N/A	ENSP00000457278.1	H3BTQ3

Frequencies

GnomAD3 genomes

AF:

0.0101

AC:

1541

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00319

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00386

Gnomad ASJ

AF:

0.0202

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0211

Gnomad FIN

AF:

0.00782

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0157

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.0127

AC:

2670

AN:

209828

AF XY:

0.0143

show subpopulations

Gnomad AFR exome

AF:

0.00290

Gnomad AMR exome

AF:

0.00485

Gnomad ASJ exome

AF:

0.0184

Gnomad EAS exome

AF:

0.000254

Gnomad FIN exome

AF:

0.00604

Gnomad NFE exome

AF:

0.0164

Gnomad OTH exome

AF:

0.0127

GnomAD4 exome

AF:

0.0164

AC:

23693

AN:

1444748

Hom.:

230

Cov.:

AF XY:

0.0167

AC XY:

12018

AN XY:

717598

show subpopulations

African (AFR)

AF:

0.00276

AC:

AN:

32962

American (AMR)

AF:

0.00525

AC:

226

AN:

43022

Ashkenazi Jewish (ASJ)

AF:

0.0194

AC:

501

AN:

25778

East Asian (EAS)

AF:

0.000235

AC:

AN:

38364

South Asian (SAS)

AF:

0.0228

AC:

1920

AN:

84086

European-Finnish (FIN)

AF:

0.00629

AC:

317

AN:

50412

Middle Eastern (MID)

AF:

0.0227

AC:

130

AN:

5720

European-Non Finnish (NFE)

AF:

0.0177

AC:

19593

AN:

1104828

Other (OTH)

AF:

0.0152

AC:

906

AN:

59576

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

1414

2828

4243

5657

7071

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

774

1548

2322

3096

3870

<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:

0.0101

AC:

1539

AN:

152288

Hom.:

Cov.:

AF XY:

0.00941

AC XY:

701

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00318

AC:

132

AN:

41562

American (AMR)

AF:

0.00386

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0202

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5182

South Asian (SAS)

AF:

0.0209

AC:

101

AN:

4826

European-Finnish (FIN)

AF:

0.00782

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0157

AC:

1068

AN:

68008

Other (OTH)

AF:

0.0104

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

163

245

326

408

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0149

Hom.:

Bravo

AF:

0.00926

TwinsUK

AF:

0.0146

AC:

ALSPAC

AF:

0.0166

AC:

ESP6500AA

AF:

0.00330

AC:

ESP6500EA

AF:

0.0144

AC:

118

ExAC

AF:

0.0123

AC:

1463

Asia WGS

AF:

0.00635

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

MetaRNN

Benign

0.018

MetaSVM

Uncertain

0.090

MutationAssessor

Pathogenic

3.8

PhyloP100

9.7

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.4

REVEL

Uncertain

0.51

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.68

MPC

0.40

ClinPred

0.065

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.69

gMVP

0.90

Mutation Taster

=77/23

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.24

Position offset: 24

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