rs1555874538

Variant names:

• chr21-45504520-AGGCCCCCC-A
• rs1555874538
• NM_001379500.1:c.2833_2840delGGCCCCCC

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_001379500.1(COL18A1):​c.2833_2840delGGCCCCCC​(p.Gly945ArgfsTer139) variant causes a frameshift change. Variant has been reported in ClinVar as Likely pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. G945G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00043 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: COL18A1 NM_001379500.1 frameshift
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.03
• Publications: 0 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 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 21-45504520-AGGCCCCCC-A is Pathogenic according to our data. Variant chr21-45504520-AGGCCCCCC-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 438063.Status of the report is no_assertion_criteria_provided, 0 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	NM_001379500.1	MANE Select	c.2833_2840delGGCCCCCC	p.Gly945ArgfsTer139	frameshift	Exon 34 of 42	NP_001366429.1
	COL18A1	NM_130444.3		c.4078_4085delGGCCCCCC	p.Gly1360ArgfsTer139	frameshift	Exon 33 of 41	NP_569711.2
	COL18A1	NM_030582.4		c.3373_3380delGGCCCCCC	p.Gly1125ArgfsTer139	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.2833_2840delGGCCCCCC	p.Gly945ArgfsTer139	frameshift	Exon 34 of 42	ENSP00000498485.1
	COL18A1	ENST00000355480.10	TSL:1	c.3373_3380delGGCCCCCC	p.Gly1125ArgfsTer139	frameshift	Exon 33 of 41	ENSP00000347665.5
	SLC19A1	ENST00000567670.5	TSL:1	c.1294-5916_1294-5909delGGGGGGCC		intron	N/A	ENSP00000457278.1

Frequencies

GnomAD3 genomes AF: 0.000569 AC: 1 AN: 1756 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0357

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000429 AC: 7 AN: 16314 Hom.: 0 AF XY: 0.000394 AC XY: 3 AN XY: 7608

African (AFR) AF: 0.00 AC: 0 AN: 1192

American (AMR) AF: 0.00 AC: 0 AN: 88

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 90

East Asian (EAS) AF: 0.0833 AC: 7 AN: 84

South Asian (SAS) AF: 0.00 AC: 0 AN: 326

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 34

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 13886

Other (OTH) AF: 0.00 AC: 0 AN: 610

GnomAD4 genome AF: 0.000569 AC: 1 AN: 1756 Hom.: 0 Cov.: 0 AF XY: 0.00113 AC XY: 1 AN XY: 888

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 1276

American (AMR) AF: 0.00 AC: 0 AN: 112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16

East Asian (EAS) AF: 0.0357 AC: 1 AN: 28

South Asian (SAS) AF: 0.00 AC: 0 AN: 8

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 86

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 216

Other (OTH) AF: 0.00 AC: 0 AN: 14

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Retinal dystrophy Pathogenic:1

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.0
Mutation Taster		=13/187	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555874538; hg19: chr21-46924434;