15-78921873-C-G

Variant names:

• chr15-78921873-C-G
• rs3129
• NM_004390.5:c.*257G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004390.5(CTSH):​c.*257G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 360,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: CTSH NM_004390.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.806
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

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.*257G>C		3_prime_UTR	Exon 12 of 12	NP_004381.2
	CTSH	NM_001411095.1		c.*257G>C		3_prime_UTR	Exon 12 of 12	NP_001398024.1	E9PKT6
	CTSH	NM_001319137.2		c.*257G>C		3_prime_UTR	Exon 13 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.*257G>C		3_prime_UTR	Exon 12 of 12	ENSP00000220166.6	P09668
	CTSH	ENST00000527715.6	TSL:1	n.3585G>C		non_coding_transcript_exon	Exon 11 of 11
	CTSH	ENST00000533777.5	TSL:1	n.*1749G>C		non_coding_transcript_exon	Exon 13 of 13	ENSP00000431879.1	A0A0B4J217

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000277 AC: 1 AN: 360710 Hom.: 0 Cov.: 0 AF XY: 0.00000534 AC XY: 1 AN XY: 187372

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 10460

American (AMR) AF: 0.00 AC: 0 AN: 14398

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11688

East Asian (EAS) AF: 0.00 AC: 0 AN: 25430

South Asian (SAS) AF: 0.00 AC: 0 AN: 31800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24436

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1664

European-Non Finnish (NFE) AF: 0.00000456 AC: 1 AN: 219120

Other (OTH) AF: 0.00 AC: 0 AN: 21714

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.2
DANN	Benign	0.65
PhyloP100		-0.81

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

Other links and lift over

dbSNP: rs3129; hg19: chr15-79214215;