Genetic Variant COL18A1:p.Val110Phe (chr21-45455858-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_130444.3(COL18A1):c.328G>T(p.Val110Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. V110V) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

COL18A1
NM_130444.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.79

Variant links:

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.927

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL18A1	NM_001379500.1 link	c.107-12384G>T		intron_variant	Intron 2 of 41	ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3 link	c.328G>T	p.Val110Phe	missense_variant	Exon 1 of 41		NP_569711.2	P39060
COL18A1	NM_030582.4 link	c.328G>T	p.Val110Phe	missense_variant	Exon 1 of 41		NP_085059.2	P39060D3DSM5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL18A1	ENST00000355480.10 link	c.328G>T	p.Val110Phe	missense_variant	Exon 1 of 41	1		ENSP00000347665.5	P39060-1
COL18A1	ENST00000651438.1 link	c.107-12384G>T		intron_variant	Intron 2 of 41		NM_001379500.1	ENSP00000498485.1	P39060-2
COL18A1	ENST00000359759.8 link	c.328G>T	p.Val110Phe	missense_variant	Exon 1 of 41	5		ENSP00000352798.4	P39060-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460856

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726750

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Uncertain

0.016

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.12

.;T

Eigen

Uncertain

0.27

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.67

T;T

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Benign

-0.86

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-2.4

N;N

REVEL

Uncertain

0.30

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0090

D;D

Polyphen

0.99

D;D

Vest4

0.58

MutPred

0.73

Loss of catalytic residue at V110 (P = 0.0929);Loss of catalytic residue at V110 (P = 0.0929);

MVP

0.81

MPC

0.088

ClinPred

0.94

GERP RS

3.7

PromoterAI

0.034

Neutral

(source)

Varity_R

0.32

gMVP

0.32

Mutation Taster

=92/8

polymorphism

(source)

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

Publications

No publications associated with this variant yet.

chr21-45455858-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over