rs12148472

chr15-78939136-T-Cchr15-78939136-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004390.5(CTSH):c.123+4A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,596,550 control chromosomes in the GnomAD database, including 13,660 homozygotes. 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: 𝑓 0.14 (1531 hom., cov: 33)
  • Exomes 𝑓: 0.13 (12129 hom.)
• Consequence: CTSH NM_004390.5 splice_donor_region, intron
• Scores: Splicing: ADA: 0.2561
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.41

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSH	NM_004390.5	c.123+4A>G		splice_donor_region_variant, intron_variant		ENST00000220166.10
CTSH	NM_001319137.2	c.-953+4A>G		splice_donor_region_variant, intron_variant
CTSH	NM_001411095.1	c.9+4A>G		splice_donor_region_variant, intron_variant
CTSH	XM_017021951.2	c.-70+4A>G		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSH	ENST00000220166.10	c.123+4A>G		splice_donor_region_variant, intron_variant		1	NM_004390.5	P1

Frequencies

GnomAD3 genomes AF: 0.137 AC: 20763 AN: 151852 Hom.: 1531 Cov.: 33

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.0648

Gnomad AMR AF: 0.0916

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.0619

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.133

GnomAD3 exomes AF: 0.121 AC: 28483 AN: 235996 Hom.: 1835 AF XY: 0.123 AC XY: 15613 AN XY: 127386

Gnomad AFR exome AF: 0.176

Gnomad AMR exome AF: 0.0771

Gnomad ASJ exome AF: 0.104

Gnomad EAS exome AF: 0.0637

Gnomad SAS exome AF: 0.148

Gnomad FIN exome AF: 0.130

Gnomad NFE exome AF: 0.127

Gnomad OTH exome AF: 0.125

GnomAD4 exome AF: 0.126 AC: 182655 AN: 1444580 Hom.: 12129 Cov.: 29 AF XY: 0.128 AC XY: 91581 AN XY: 718284

Gnomad4 AFR exome AF: 0.178

Gnomad4 AMR exome AF: 0.0768

Gnomad4 ASJ exome AF: 0.104

Gnomad4 EAS exome AF: 0.0622

Gnomad4 SAS exome AF: 0.144

Gnomad4 FIN exome AF: 0.138

Gnomad4 NFE exome AF: 0.128

Gnomad4 OTH exome AF: 0.127

GnomAD4 genome AF: 0.137 AC: 20779 AN: 151970 Hom.: 1531 Cov.: 33 AF XY: 0.135 AC XY: 10058 AN XY: 74268

Gnomad4 AFR AF: 0.180

Gnomad4 AMR AF: 0.0916

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.0616

Gnomad4 SAS AF: 0.149

Gnomad4 FIN AF: 0.132

Gnomad4 NFE AF: 0.129

Gnomad4 OTH AF: 0.131

Alfa AF: 0.124 Hom.: 2084

Bravo AF: 0.133

Asia WGS AF: 0.111 AC: 386 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	17
Dann	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.26
dbscSNV1_RF	Benign	0.21
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs12148472; hg19: chr15-79231478; COSMIC: COSV54986054; COSMIC: COSV54986054;