15-78935726-A-G

Variant names:

• chr15-78935726-A-G
• NM_004390.5:c.254T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004390.5(CTSH):​c.254T>C​(p.Met85Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTSH NM_004390.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.70

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSH	NM_004390.5	c.254T>C	p.Met85Thr	missense_variant	Exon 4 of 12	ENST00000220166.10	NP_004381.2
CTSH	NM_001411095.1	c.140T>C	p.Met47Thr	missense_variant	Exon 4 of 12		NP_001398024.1
CTSH	XM_017021951.2	c.200T>C	p.Met67Thr	missense_variant	Exon 5 of 13		XP_016877440.1
CTSH	NM_001319137.2	c.-684T>C		5_prime_UTR_variant	Exon 5 of 13		NP_001306066.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSH	ENST00000220166.10	c.254T>C	p.Met85Thr	missense_variant	Exon 4 of 12	1	NM_004390.5	ENSP00000220166.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.254T>C (p.M85T) alteration is located in exon 4 (coding exon 4) of the CTSH gene. This alteration results from a T to C substitution at nucleotide position 254, causing the methionine (M) at amino acid position 85 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D;.;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	3.6	H;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-4.1	D;.;D
REVEL	Uncertain	0.50
Sift	Benign	0.057	T;.;D
Sift4G	Uncertain	0.059	T;T;.
Vest4		0.47
MutPred		0.81		Loss of catalytic residue at M85 (P = 0.0897);.;.;
MVP		0.95
MPC		0.44
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.67
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-79228068;