NM_004390.5:c.607G>C

Variant names:

• chr15-78929435-C-G
• NM_004390.5:c.607G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004390.5(CTSH):​c.607G>C​(p.Asp203His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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: 2.79
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3875395).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004390.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSH	NM_004390.5	MANE Select	c.607G>C	p.Asp203His	missense	Exon 8 of 12	NP_004381.2
	CTSH	NM_001411095.1		c.493G>C	p.Asp165His	missense	Exon 8 of 12	NP_001398024.1	E9PKT6
	CTSH	NM_001319137.2		c.205G>C	p.Asp69His	missense	Exon 9 of 13	NP_001306066.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSH	ENST00000220166.10	TSL:1 MANE Select	c.607G>C	p.Asp203His	missense	Exon 8 of 12	ENSP00000220166.6	P09668
	CTSH	ENST00000615999.5	TSL:1	c.607G>C	p.Asp203His	missense	Exon 8 of 13	ENSP00000483303.2	A0A087X0D5
	CTSH	ENST00000527715.6	TSL:1	n.655G>C		non_coding_transcript_exon	Exon 8 of 11

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.8
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.16
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.052	T
Polyphen		0.94	P
Vest4		0.37
MutPred		0.53		Loss of sheet (P = 0.1158)
MVP		0.11
MPC		0.56
ClinPred		0.97	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.63
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

hg19: chr15-79221777;