chr4-108824222-G-C
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting
The NM_198721.4(COL25A1):c.1797C>G(p.Phe599Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,611,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
COL25A1
NM_198721.4 missense
NM_198721.4 missense
Scores
1
5
7
Clinical Significance
Conservation
PhyloP100: 0.602
Genes affected
COL25A1 (HGNC:18603): (collagen type XXV alpha 1 chain) This gene encodes a brain-specific membrane associated collagen. A product of proteolytic processing of the encoded protein, CLAC (collagenous Alzheimer amyloid plaque component), binds to amyloid beta-peptides found in Alzheimer amyloid plaques but CLAC inhibits rather than facilitates amyloid fibril elongation (PMID: 16300410). A study of over-expression of this collagen in mice, however, found changes in pathology and behavior suggesting that the encoded protein may promote amyloid plaque formation (PMID: 19548013). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.16636616).
BS1
?
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000158 (23/1459044) while in subpopulation MID AF= 0.000348 (2/5752). AF 95% confidence interval is 0.0000611. There are 0 homozygotes in gnomad4_exome. There are 6 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL25A1 | NM_198721.4 | c.1797C>G | p.Phe599Leu | missense_variant | 35/38 | ENST00000399132.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL25A1 | ENST00000399132.6 | c.1797C>G | p.Phe599Leu | missense_variant | 35/38 | 5 | NM_198721.4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152134Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000162 AC: 4AN: 246394Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 133850
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GnomAD4 exome AF: 0.0000158 AC: 23AN: 1459044Hom.: 0 Cov.: 31 AF XY: 0.00000827 AC XY: 6AN XY: 725838
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 21, 2017 | The F599L variant in the COL25A1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The F599L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Phenylalanine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret F599L as a variant of uncertain significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;D;T;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Uncertain
T
MutationTaster
Benign
D;N;N
PrimateAI
Uncertain
T
Polyphen
0.28, 0.23
.;.;B;.;B
Vest4
0.17, 0.17, 0.13
MutPred
0.35
.;.;Loss of methylation at R603 (P = 0.1526);.;Loss of methylation at R603 (P = 0.1526);
MVP
0.79
MPC
0.36
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at