rs11638844

chr15-78939176-A-Gchr15-78939176-A-T

Variant summary

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

The NM_004390.5(CTSH):c.92-5T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.645 in 1,584,466 control chromosomes in the GnomAD database, including 337,609 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.54 (24396 hom., cov: 32)
  • Exomes 𝑓: 0.66 (313213 hom.)
• Consequence: CTSH NM_004390.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003227
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.199

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=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.669 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSH	NM_004390.5	c.92-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000220166.10
CTSH	NM_001319137.2	c.-984-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
CTSH	NM_001411095.1	c.-23-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
CTSH	XM_017021951.2	c.-101-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSH	ENST00000220166.10	c.92-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004390.5	P1

Frequencies

GnomAD3 genomes AF: 0.538 AC: 81633 AN: 151620 Hom.: 24380 Cov.: 32

Gnomad AFR AF: 0.266

Gnomad AMI AF: 0.710

Gnomad AMR AF: 0.576

Gnomad ASJ AF: 0.664

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.627

Gnomad FIN AF: 0.610

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.675

Gnomad OTH AF: 0.543

GnomAD3 exomes AF: 0.603 AC: 139403 AN: 231282 Hom.: 43517 AF XY: 0.613 AC XY: 76679 AN XY: 125110

Gnomad AFR exome AF: 0.254

Gnomad AMR exome AF: 0.569

Gnomad ASJ exome AF: 0.668

Gnomad EAS exome AF: 0.468

Gnomad SAS exome AF: 0.632

Gnomad FIN exome AF: 0.618

Gnomad NFE exome AF: 0.668

Gnomad OTH exome AF: 0.614

GnomAD4 exome AF: 0.656 AC: 939748 AN: 1432728 Hom.: 313213 Cov.: 32 AF XY: 0.657 AC XY: 467952 AN XY: 712566

Gnomad4 AFR exome AF: 0.254

Gnomad4 AMR exome AF: 0.574

Gnomad4 ASJ exome AF: 0.673

Gnomad4 EAS exome AF: 0.450

Gnomad4 SAS exome AF: 0.643

Gnomad4 FIN exome AF: 0.613

Gnomad4 NFE exome AF: 0.682

Gnomad4 OTH exome AF: 0.634

GnomAD4 genome AF: 0.538 AC: 81683 AN: 151738 Hom.: 24396 Cov.: 32 AF XY: 0.538 AC XY: 39912 AN XY: 74128

Gnomad4 AFR AF: 0.266

Gnomad4 AMR AF: 0.576

Gnomad4 ASJ AF: 0.664

Gnomad4 EAS AF: 0.472

Gnomad4 SAS AF: 0.630

Gnomad4 FIN AF: 0.610

Gnomad4 NFE AF: 0.675

Gnomad4 OTH AF: 0.547

Alfa AF: 0.617 Hom.: 19630

Bravo AF: 0.524

Asia WGS AF: 0.542 AC: 1884 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.55
Dann	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000032
dbscSNV1_RF	Benign	0.0
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: rs11638844; hg19: chr15-79231518; COSMIC: COSV54984200; COSMIC: COSV54984200;