15-78927771-C-A
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_004390.5(CTSH):c.641G>T(p.Cys214Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000173 in 1,614,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
CTSH
NM_004390.5 missense
NM_004390.5 missense
Scores
12
6
1
Clinical Significance
Conservation
PhyloP100: 6.18
Genes affected
CTSH (HGNC:2535): (cathepsin H) The protein encoded by this gene is a lysosomal cysteine proteinase important in the overall degradation of lysosomal proteins. It is composed of a dimer of disulfide-linked heavy and light chains, both produced from a single protein precursor. The encoded protein, which belongs to the peptidase C1 protein family, can act both as an aminopeptidase and as an endopeptidase. Increased expression of this gene has been correlated with malignant progression of prostate tumors. Alternate splicing of this gene results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.991
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CTSH | NM_004390.5 | c.641G>T | p.Cys214Phe | missense_variant | 9/12 | ENST00000220166.10 | |
CTSH | NM_001411095.1 | c.527G>T | p.Cys176Phe | missense_variant | 9/12 | ||
CTSH | NM_001319137.2 | c.239G>T | p.Cys80Phe | missense_variant | 10/13 | ||
CTSH | XM_017021951.2 | c.587G>T | p.Cys196Phe | missense_variant | 10/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CTSH | ENST00000220166.10 | c.641G>T | p.Cys214Phe | missense_variant | 9/12 | 1 | NM_004390.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000328 AC: 5AN: 152212Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251440Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135900
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GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461788Hom.: 0 Cov.: 30 AF XY: 0.0000165 AC XY: 12AN XY: 727192
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GnomAD4 genome AF: 0.0000328 AC: 5AN: 152212Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74352
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 21, 2023 | The c.641G>T (p.C214F) alteration is located in exon 9 (coding exon 9) of the CTSH gene. This alteration results from a G to T substitution at nucleotide position 641, causing the cysteine (C) at amino acid position 214 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.
REVEL
Pathogenic
Sift
Pathogenic
D;.
Sift4G
Pathogenic
D;D
Polyphen
D;.
Vest4
MVP
MPC
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