chr21-45456763-C-G

Variant names:

• chr21-45456763-C-G
• rs764709181
• NM_001379500.1:c.107-11479C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_130444.3(COL18A1):​c.1233C>G​(p.Phe411Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000216 in 1,388,700 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: COL18A1 NM_130444.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.42
• Publications: 2 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.107-11479C>G		intron	N/A	NP_001366429.1
	COL18A1	NM_130444.3		c.1233C>G	p.Phe411Leu	missense	Exon 1 of 41	NP_569711.2
	COL18A1	NM_030582.4		c.646+587C>G		intron	N/A	NP_085059.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.107-11479C>G		intron	N/A	ENSP00000498485.1
	COL18A1	ENST00000355480.10	TSL:1	c.646+587C>G		intron	N/A	ENSP00000347665.5
	COL18A1	ENST00000359759.8	TSL:5	c.1233C>G	p.Phe411Leu	missense	Exon 1 of 41	ENSP00000352798.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000216 AC: 3 AN: 1388700 Hom.: 0 Cov.: 36 AF XY: 0.00000292 AC XY: 2 AN XY: 684960

African (AFR) AF: 0.00 AC: 0 AN: 31332

American (AMR) AF: 0.00 AC: 0 AN: 35532

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25058

East Asian (EAS) AF: 0.0000843 AC: 3 AN: 35576

South Asian (SAS) AF: 0.00 AC: 0 AN: 79050

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5680

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1077096

Other (OTH) AF: 0.00 AC: 0 AN: 57766

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.49	T
M_CAP	Pathogenic	0.40	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Uncertain	0.15	D
PhyloP100		1.4
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.61
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.026	D
Polyphen		1.0	D
Vest4		0.23
MutPred		0.61		Gain of helix (P = 0.0696)
MVP		0.85
ClinPred		0.86	D
GERP RS		4.3
Varity_R		0.23
gMVP		0.15
Mutation Taster		=87/13	polymorphism

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: rs764709181; hg19: chr21-46876677;