21-45455650-T-A

Variant names:

• chr21-45455650-T-A
• rs914230
• ENST00000355480.10:c.120T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_130444.3(COL18A1):​c.120T>A​(p.His40Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H40H) has been classified as Benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: COL18A1 NM_130444.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0690
• Publications: 19 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• 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_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.055250853).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	NM_001379500.1	MANE Select	c.107-12592T>A		intron	N/A	NP_001366429.1	P39060-2
	COL18A1	NM_130444.3		c.120T>A	p.His40Gln	missense	Exon 1 of 41	NP_569711.2
	COL18A1	NM_030582.4		c.120T>A	p.His40Gln	missense	Exon 1 of 41	NP_085059.2	A0AAG2UXZ5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000355480.10	TSL:1	c.120T>A	p.His40Gln	missense	Exon 1 of 41	ENSP00000347665.5	P39060-1
	COL18A1	ENST00000651438.1	MANE Select	c.107-12592T>A		intron	N/A	ENSP00000498485.1	P39060-2
	COL18A1	ENST00000359759.8	TSL:5	c.120T>A	p.His40Gln	missense	Exon 1 of 41	ENSP00000352798.4	P39060-3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 86

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.9
DANN	Benign	0.51
DEOGEN2	Benign	0.034	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.069
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.047
Sift	Benign	0.38	T
Sift4G	Benign	0.46	T
Polyphen		0.0	B
Vest4		0.059
MutPred		0.45		Loss of glycosylation at T38 (P = 0.0623)
MVP		0.15
MPC		0.068
ClinPred		0.15	T
GERP RS		1.7
PromoterAI		0.094	Neutral
Varity_R		0.034
gMVP		0.056
Mutation Taster		=100/0	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: rs914230; hg19: chr21-46875564;