chr4-108824212-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.1807C>T(p.Arg603Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000639 in 1,612,984 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: 0.000065 ( 0 hom. )
Consequence
COL25A1
NM_198721.4 missense
NM_198721.4 missense
Scores
2
7
4
Clinical Significance
Conservation
PhyloP100: 6.62
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 mid. gnomad4_exome allele frequency = 0.000065 (95/1460870) while in subpopulation MID AF= 0.000173 (1/5764). AF 95% confidence interval is 0.0000571. There are 0 homozygotes in gnomad4_exome. There are 49 alleles in male gnomad4_exome 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.1807C>T | p.Arg603Trp | missense_variant | 35/38 | ENST00000399132.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL25A1 | ENST00000399132.6 | c.1807C>T | p.Arg603Trp | missense_variant | 35/38 | 5 | NM_198721.4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152114Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000686 AC: 17AN: 247738Hom.: 0 AF XY: 0.0000669 AC XY: 9AN XY: 134542
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GnomAD4 exome AF: 0.0000650 AC: 95AN: 1460870Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 49AN XY: 726730
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GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152114Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74308
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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 13, 2022 | The c.1807C>T (p.R603W) alteration is located in exon 35 (coding exon 34) of the COL25A1 gene. This alteration results from a C to T substitution at nucleotide position 1807, causing the arginine (R) at amino acid position 603 to be replaced by a tryptophan (W). 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
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
Polyphen
1.0
.;.;D;.;D
Vest4
0.57, 0.56, 0.48, 0.49
MutPred
0.58
.;.;Loss of methylation at R603 (P = 0.0185);.;Loss of methylation at R603 (P = 0.0185);
MVP
0.94
MPC
1.0
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