NM_001379500.1:c.3959_3960insTGCC

Variant names:

• chr21-45512337-G-GTGCC
• rs1555877107
• NM_001379500.1:c.3959_3960insTGCC

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_001379500.1(COL18A1):​c.3959_3960insTGCC​(p.Cys1321AlafsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. S1320S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL18A1 NM_001379500.1 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.12
• 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: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0149 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 21-45512337-G-GTGCC is Pathogenic according to our data. Variant chr21-45512337-G-GTGCC is described in ClinVar as Pathogenic. ClinVar VariationId is 548657.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.3959_3960insTGCC	p.Cys1321AlafsTer12	frameshift	Exon 42 of 42	NP_001366429.1
	COL18A1	NM_130444.3		c.5204_5205insTGCC	p.Cys1736AlafsTer12	frameshift	Exon 41 of 41	NP_569711.2
	COL18A1	NM_030582.4		c.4499_4500insTGCC	p.Cys1501AlafsTer12	frameshift	Exon 41 of 41	NP_085059.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.3959_3960insTGCC	p.Cys1321AlafsTer12	frameshift	Exon 42 of 42	ENSP00000498485.1
	COL18A1	ENST00000355480.10	TSL:1	c.4499_4500insTGCC	p.Cys1501AlafsTer12	frameshift	Exon 41 of 41	ENSP00000347665.5
	SLC19A1	ENST00000567670.5	TSL:1	c.1293+13479_1293+13480insGGCA		intron	N/A	ENSP00000457278.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Knobloch syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1555877107; hg19: chr21-46932251;