21-45504470-G-C

Variant names:

• chr21-45504470-G-C
• rs187721798
• NM_001379500.1:c.2782G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001379500.1(COL18A1):​c.2782G>C​(p.Gly928Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000894 in 1,607,028 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G928G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0047 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00050 (7 hom.)
• Consequence: COL18A1 NM_001379500.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.95
• Publications: 3 publications found

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]

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.008393288).
• BP6: Variant 21-45504470-G-C is Benign according to our data. Variant chr21-45504470-G-C is described in ClinVar as Benign. ClinVar VariationId is 447121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0047 (710/151118) while in subpopulation AFR AF = 0.0164 (676/41148). AF 95% confidence interval is 0.0154. There are 7 homozygotes in GnomAd4. There are 331 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	NM_001379500.1	MANE Select	c.2782G>C	p.Gly928Arg	missense	Exon 34 of 42	NP_001366429.1	P39060-2
	COL18A1	NM_130444.3		c.4027G>C	p.Gly1343Arg	missense	Exon 33 of 41	NP_569711.2
	COL18A1	NM_030582.4		c.3322G>C	p.Gly1108Arg	missense	Exon 33 of 41	NP_085059.2	A0AAG2UXZ5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.2782G>C	p.Gly928Arg	missense	Exon 34 of 42	ENSP00000498485.1	P39060-2
	COL18A1	ENST00000355480.10	TSL:1	c.3322G>C	p.Gly1108Arg	missense	Exon 33 of 41	ENSP00000347665.5	P39060-1
	SLC19A1	ENST00000567670.5	TSL:1	c.1294-5858C>G		intron	N/A	ENSP00000457278.1	H3BTQ3

Frequencies

GnomAD3 genomes AF: 0.00470 AC: 709 AN: 151000 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0165

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00152

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.00435

GnomAD2 exomes AF: 0.00115 AC: 274 AN: 237460 AF XY: 0.000885

Gnomad AFR exome AF: 0.0169

Gnomad AMR exome AF: 0.00109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000378

Gnomad OTH exome AF: 0.000693

GnomAD4 exome AF: 0.000499 AC: 726 AN: 1455910 Hom.: 7 Cov.: 32 AF XY: 0.000406 AC XY: 294 AN XY: 724276

African (AFR) AF: 0.0171 AC: 571 AN: 33378

American (AMR) AF: 0.00123 AC: 55 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26056

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 86064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51806

Middle Eastern (MID) AF: 0.000564 AC: 3 AN: 5316

European-Non Finnish (NFE) AF: 0.0000361 AC: 40 AN: 1108994

Other (OTH) AF: 0.000899 AC: 54 AN: 60034

GnomAD4 genome AF: 0.00470 AC: 710 AN: 151118 Hom.: 7 Cov.: 33 AF XY: 0.00448 AC XY: 331 AN XY: 73854

African (AFR) AF: 0.0164 AC: 676 AN: 41148

American (AMR) AF: 0.00152 AC: 23 AN: 15178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5040

South Asian (SAS) AF: 0.00 AC: 0 AN: 4780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67702

Other (OTH) AF: 0.00430 AC: 9 AN: 2092

Alfa AF: 0.000196 Hom.: 7

Bravo AF: 0.00536

ExAC AF: 0.00147 AC: 172

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	COL18A1-related disorder (1)
-	-	1	Knobloch syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0084	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		4.9
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.75
MVP		0.97
MPC		0.44
ClinPred		0.056	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.73
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs187721798; hg19: chr21-46924384; COSMIC: COSV60590585; COSMIC: COSV60590585;