rs1114167359

Variant names:

• chr21-45481964-G-T
• rs1114167359
• NM_001379500.1:c.1613G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001379500.1(COL18A1):​c.1613G>T​(p.Gly538Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: COL18A1 NM_001379500.1 missense, splice_region
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.954
• 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]

COL18A1 Gene-Disease associations (from GenCC):

• Knobloch syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Knobloch syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet
• hereditary glaucoma, primary closed-angle

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 21-45481964-G-T is Pathogenic according to our data. Variant chr21-45481964-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 427899.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.1613G>T	p.Gly538Val	missense_variant, splice_region_variant	Exon 14 of 42	ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3	c.2858G>T	p.Gly953Val	missense_variant, splice_region_variant	Exon 13 of 41		NP_569711.2
COL18A1	NM_030582.4	c.2153G>T	p.Gly718Val	missense_variant, splice_region_variant	Exon 13 of 41		NP_085059.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.1613G>T	p.Gly538Val	missense_variant, splice_region_variant	Exon 14 of 42		NM_001379500.1	ENSP00000498485.1
COL18A1	ENST00000355480.10	c.2153G>T	p.Gly718Val	missense_variant, splice_region_variant	Exon 13 of 41	1		ENSP00000347665.5
COL18A1	ENST00000359759.8	c.2858G>T	p.Gly953Val	missense_variant, splice_region_variant	Exon 13 of 41	5		ENSP00000352798.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Knobloch syndrome Pathogenic:1

Feb 03, 2017

Shenzhen Institute of Pediatrics, Shenzhen Children's Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	.;.;D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.3	.;.;H
PhyloP100		0.95
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.0	D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.018	D;D;D
Sift4G	Uncertain	0.031	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.93
MutPred		1.0		.;.;Loss of glycosylation at P952 (P = 0.0782);
MVP		0.98
MPC		0.44
ClinPred		0.99	D
GERP RS		3.8
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.53
gMVP		0.87
Mutation Taster		=48/52	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1114167359; hg19: chr21-46901878;