chr21-45493561-C-T

Variant names:

• chr21-45493561-C-T
• rs786205554
• NM_001379500.1:c.2338C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001379500.1(COL18A1):​c.2338C>T​(p.Gln780*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,402,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: COL18A1 NM_001379500.1 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.724
• Publications: 1 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 21-45493561-C-T is Pathogenic according to our data. Variant chr21-45493561-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 191166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2338C>T	p.Gln780*	stop_gained	Exon 26 of 42	NP_001366429.1	P39060-2
	COL18A1	NM_130444.3		c.3583C>T	p.Gln1195*	stop_gained	Exon 25 of 41	NP_569711.2
	COL18A1	NM_030582.4		c.2878C>T	p.Gln960*	stop_gained	Exon 25 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.2338C>T	p.Gln780*	stop_gained	Exon 26 of 42	ENSP00000498485.1	P39060-2
	COL18A1	ENST00000355480.10	TSL:1	c.2878C>T	p.Gln960*	stop_gained	Exon 25 of 41	ENSP00000347665.5	P39060-1
	COL18A1	ENST00000359759.8	TSL:5	c.3583C>T	p.Gln1195*	stop_gained	Exon 25 of 41	ENSP00000352798.4	P39060-3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000632 AC: 1 AN: 158144 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000891

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1402814 Hom.: 0 Cov.: 32 AF XY: 0.00000144 AC XY: 1 AN XY: 692544

African (AFR) AF: 0.00 AC: 0 AN: 31764

American (AMR) AF: 0.00 AC: 0 AN: 36258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25198

East Asian (EAS) AF: 0.00 AC: 0 AN: 36040

South Asian (SAS) AF: 0.00 AC: 0 AN: 79528

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5608

European-Non Finnish (NFE) AF: 9.24e-7 AC: 1 AN: 1081918

Other (OTH) AF: 0.00 AC: 0 AN: 58202

GnomAD4 genome Cov.: 34

Alfa AF: 0.00000588 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Benign	-0.024
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.10	N
PhyloP100		0.72
Vest4		0.81
GERP RS		1.4
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Mutation Taster		=3/197	disease causing (ClinVar)

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: rs786205554; hg19: chr21-46913475;