chr21-45504504-GC-G

Variant names:

• chr21-45504504-GC-G
• rs769882681
• NM_001379500.1:c.2823delC

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_130444.3(COL18A1):​c.4068delC​(p.Gly1357AlafsTer89) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000194 in 1,392,616 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P1356P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: COL18A1 NM_130444.3 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.37
• Publications: 5 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]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130444.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	NM_001379500.1	MANE Select	c.2823delC	p.Gly942AlafsTer89	frameshift	Exon 34 of 42	NP_001366429.1
	COL18A1	NM_130444.3		c.4068delC	p.Gly1357AlafsTer89	frameshift	Exon 33 of 41	NP_569711.2
	COL18A1	NM_030582.4		c.3363delC	p.Gly1122AlafsTer89	frameshift	Exon 33 of 41	NP_085059.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.2823delC	p.Gly942AlafsTer89	frameshift	Exon 34 of 42	ENSP00000498485.1
	COL18A1	ENST00000355480.10	TSL:1	c.3363delC	p.Gly1122AlafsTer89	frameshift	Exon 33 of 41	ENSP00000347665.5
	SLC19A1	ENST00000567670.5	TSL:1	c.1294-5893delG		intron	N/A	ENSP00000457278.1

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 4 AN: 3200 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00323

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000360 AC: 2 AN: 55592 AF XY: 0.0000638

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000105

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000166 AC: 23 AN: 1389416 Hom.: 0 Cov.: 30 AF XY: 0.0000174 AC XY: 12 AN XY: 690766

African (AFR) AF: 0.00 AC: 0 AN: 31290

American (AMR) AF: 0.00 AC: 0 AN: 40148

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25516

East Asian (EAS) AF: 0.00 AC: 0 AN: 38334

South Asian (SAS) AF: 0.00 AC: 0 AN: 82786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4630

European-Non Finnish (NFE) AF: 0.0000198 AC: 21 AN: 1059696

Other (OTH) AF: 0.0000348 AC: 2 AN: 57482

GnomAD4 genome AF: 0.00125 AC: 4 AN: 3200 Hom.: 0 Cov.: 29 AF XY: 0.00193 AC XY: 3 AN XY: 1552

African (AFR) AF: 0.00 AC: 0 AN: 1372

American (AMR) AF: 0.00 AC: 0 AN: 274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 42

East Asian (EAS) AF: 0.00 AC: 0 AN: 50

South Asian (SAS) AF: 0.00 AC: 0 AN: 34

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 8

European-Non Finnish (NFE) AF: 0.00323 AC: 4 AN: 1240

Other (OTH) AF: 0.00 AC: 0 AN: 20

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.4
Mutation Taster		=4/196	disease causing (fs/PTC)

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: rs769882681; hg19: chr21-46924418;