chr4-108844532-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting
The NM_198721.4(COL25A1):c.1616C>T(p.Pro539Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000105 in 1,613,756 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
COL25A1
NM_198721.4 missense
NM_198721.4 missense
Scores
1
10
2
Clinical Significance
Conservation
PhyloP100: 4.56
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 1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BS1
?
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000526 (8/152154) while in subpopulation AMR AF= 0.000393 (6/15276). AF 95% confidence interval is 0.00017. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 32. 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.1616C>T | p.Pro539Leu | missense_variant | 30/38 | ENST00000399132.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL25A1 | ENST00000399132.6 | c.1616C>T | p.Pro539Leu | missense_variant | 30/38 | 5 | NM_198721.4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152154Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000805 AC: 2AN: 248598Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 134900
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GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461602Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727112
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GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152154Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74316
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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 | Dec 09, 2023 | The c.1616C>T (p.P539L) alteration is located in exon 30 (coding exon 29) of the COL25A1 gene. This alteration results from a C to T substitution at nucleotide position 1616, causing the proline (P) at amino acid position 539 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
Uncertain
D
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
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, 0.99
.;.;D;.;D
Vest4
0.45, 0.48, 0.52, 0.47
MutPred
Loss of glycosylation at P539 (P = 0.036);.;Loss of glycosylation at P539 (P = 0.036);.;Loss of glycosylation at P539 (P = 0.036);
MVP
0.93
MPC
0.40
ClinPred
D
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