4-108846140-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_198721.4(COL25A1):c.1514C>T(p.Pro505Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,592,660 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000015 ( 0 hom. )
Consequence
COL25A1
NM_198721.4 missense, splice_region
NM_198721.4 missense, splice_region
Scores
6
5
2
Splicing: ADA: 0.9870
2
Clinical Significance
Conservation
PhyloP100: 7.34
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 Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL25A1 | NM_198721.4 | c.1514C>T | p.Pro505Leu | missense_variant, splice_region_variant | 28/38 | ENST00000399132.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL25A1 | ENST00000399132.6 | c.1514C>T | p.Pro505Leu | missense_variant, splice_region_variant | 28/38 | 5 | NM_198721.4 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151994Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000241 AC: 6AN: 249310Hom.: 0 AF XY: 0.0000370 AC XY: 5AN XY: 135262
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GnomAD4 exome AF: 0.0000146 AC: 21AN: 1440666Hom.: 0 Cov.: 27 AF XY: 0.0000167 AC XY: 12AN XY: 718278
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GnomAD4 genome AF: 0.0000132 AC: 2AN: 151994Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74222
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 01, 2023 | The c.1514C>T (p.P505L) alteration is located in exon 28 (coding exon 27) of the COL25A1 gene. This alteration results from a C to T substitution at nucleotide position 1514, causing the proline (P) at amino acid position 505 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
Polyphen
1.0
.;.;D;.;D
Vest4
0.53, 0.63, 0.49, 0.56
MutPred
Gain of stability (P = 0.0932);.;Gain of stability (P = 0.0932);.;Gain of stability (P = 0.0932);
MVP
0.93
MPC
0.96
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at