15-78925362-T-A

Variant names:

• chr15-78925362-T-A
• NM_004390.5:c.778A>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004390.5(CTSH):​c.778A>T​(p.Met260Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CTSH NM_004390.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.601

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16223136).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSH	NM_004390.5	c.778A>T	p.Met260Leu	missense_variant	Exon 10 of 12	ENST00000220166.10	NP_004381.2
CTSH	NM_001411095.1	c.664A>T	p.Met222Leu	missense_variant	Exon 10 of 12		NP_001398024.1
CTSH	NM_001319137.2	c.376A>T	p.Met126Leu	missense_variant	Exon 11 of 13		NP_001306066.1
CTSH	XM_017021951.2	c.724A>T	p.Met242Leu	missense_variant	Exon 11 of 13		XP_016877440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSH	ENST00000220166.10	c.778A>T	p.Met260Leu	missense_variant	Exon 10 of 12	1	NM_004390.5	ENSP00000220166.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461026 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726890

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	7.2
DANN	Benign	0.59
DEOGEN2	Uncertain	0.45	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.91
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.28	N;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.2	N;.
REVEL	Benign	0.25
Sift	Benign	0.30	T;.
Sift4G	Benign	0.79	T;T
Polyphen		0.0010	B;.
Vest4		0.21
MutPred		0.61		Gain of helix (P = 0.132);.;
MVP		0.31
MPC		0.13
ClinPred		0.27	T
GERP RS		-0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.45
gMVP		0.52

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: chr15-79217704;