dbSNP rs564134000: COL18A1:p.Gly930Gly (chr21-45504478-C-T) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_001379500.1(COL18A1):c.2790C>T(p.Gly930Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000232 in 1,603,322 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00077 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00018 ( 2 hom. )

Consequence

COL18A1
NM_001379500.1 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -3.46

Publications

0 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 -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 21-45504478-C-T is Benign according to our data. Variant chr21-45504478-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 447122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.45 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD 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.2790C>T	p.Gly930Gly	synonymous	Exon 34 of 42	NP_001366429.1	P39060-2
COL18A1	NM_130444.3		c.4035C>T	p.Gly1345Gly	synonymous	Exon 33 of 41	NP_569711.2
COL18A1	NM_030582.4		c.3330C>T	p.Gly1110Gly	synonymous	Exon 33 of 41	NP_085059.2	A0AAG2UXZ5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL18A1	ENST00000651438.1	MANE Select	c.2790C>T	p.Gly930Gly	synonymous	Exon 34 of 42	ENSP00000498485.1	P39060-2
COL18A1	ENST00000355480.10	TSL:1	c.3330C>T	p.Gly1110Gly	synonymous	Exon 33 of 41	ENSP00000347665.5	P39060-1
SLC19A1	ENST00000567670.5	TSL:1	c.1294-5866G>A		intron	N/A	ENSP00000457278.1	H3BTQ3

Frequencies

GnomAD3 genomes

AF:

0.000762

AC:

112

AN:

146916

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00251

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000136

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00185

Gnomad SAS

AF:

0.000218

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000150

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000468

AC:

110

AN:

235004

AF XY:

0.000431

show subpopulations

Gnomad AFR exome

AF:

0.00332

Gnomad AMR exome

AF:

0.000472

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00114

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000479

Gnomad OTH exome

AF:

0.000350

GnomAD4 exome

AF:

0.000178

AC:

259

AN:

1456294

Hom.:

Cov.:

AF XY:

0.000178

AC XY:

129

AN XY:

724374

show subpopulations

African (AFR)

AF:

0.00327

AC:

109

AN:

33384

American (AMR)

AF:

0.000494

AC:

AN:

44574

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26068

East Asian (EAS)

AF:

0.000580

AC:

AN:

39660

South Asian (SAS)

AF:

0.000860

AC:

AN:

86036

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51734

Middle Eastern (MID)

AF:

0.000192

AC:

AN:

5206

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1109636

Other (OTH)

AF:

0.000267

AC:

AN:

59996

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.000769

AC:

113

AN:

147028

Hom.:

Cov.:

AF XY:

0.000726

AC XY:

AN XY:

71588

show subpopulations

African (AFR)

AF:

0.00253

AC:

100

AN:

39488

American (AMR)

AF:

0.000136

AC:

AN:

14694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3454

East Asian (EAS)

AF:

0.00186

AC:

AN:

4838

South Asian (SAS)

AF:

0.000218

AC:

AN:

4588

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9948

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.0000150

AC:

AN:

66830

Other (OTH)

AF:

0.00

AC:

AN:

2014

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000290

Hom.:

Bravo

AF:

0.000979

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Knobloch syndrome (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.30

(source)

DANN

Benign

0.63

PhyloP100

-3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=97/3

polymorphism

(source)

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

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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