rs13345

Positions:

• chr15-78932405-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_004390.5(CTSH):​c.459G>A​(p.Ala153=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 1,613,418 control chromosomes in the GnomAD database, including 36,517 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 0.27 (6576 hom., cov: 32)
  • Exomes 𝑓: 0.19 (29941 hom.)
• Consequence: CTSH NM_004390.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -7.29

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP7: Synonymous conserved (PhyloP=-7.29 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.44 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSH	NM_004390.5	c.459G>A	p.Ala153=	synonymous_variant	6/12	ENST00000220166.10
CTSH	NM_001411095.1	c.345G>A	p.Ala115=	synonymous_variant	6/12
CTSH	XM_017021951.2	c.405G>A	p.Ala135=	synonymous_variant	7/13
CTSH	NM_001319137.2	c.-479G>A		5_prime_UTR_variant	7/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSH	ENST00000220166.10	c.459G>A	p.Ala153=	synonymous_variant	6/12	1	NM_004390.5	P1

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40878 AN: 151888 Hom.: 6572 Cov.: 32

Gnomad AFR AF: 0.445

Gnomad AMI AF: 0.227

Gnomad AMR AF: 0.240

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.320

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.186

Gnomad OTH AF: 0.286

GnomAD3 exomes AF: 0.215 AC: 54046 AN: 251280 Hom.: 6676 AF XY: 0.210 AC XY: 28573 AN XY: 135826

Gnomad AFR exome AF: 0.453

Gnomad AMR exome AF: 0.190

Gnomad ASJ exome AF: 0.213

Gnomad EAS exome AF: 0.326

Gnomad SAS exome AF: 0.162

Gnomad FIN exome AF: 0.189

Gnomad NFE exome AF: 0.190

Gnomad OTH exome AF: 0.216

GnomAD4 exome AF: 0.194 AC: 283877 AN: 1461412 Hom.: 29941 Cov.: 32 AF XY: 0.193 AC XY: 140195 AN XY: 727020

Gnomad4 AFR exome AF: 0.459

Gnomad4 AMR exome AF: 0.194

Gnomad4 ASJ exome AF: 0.210

Gnomad4 EAS exome AF: 0.331

Gnomad4 SAS exome AF: 0.166

Gnomad4 FIN exome AF: 0.190

Gnomad4 NFE exome AF: 0.182

Gnomad4 OTH exome AF: 0.211

GnomAD4 genome AF: 0.269 AC: 40915 AN: 152006 Hom.: 6576 Cov.: 32 AF XY: 0.266 AC XY: 19729 AN XY: 74286

Gnomad4 AFR AF: 0.445

Gnomad4 AMR AF: 0.240

Gnomad4 ASJ AF: 0.219

Gnomad4 EAS AF: 0.319

Gnomad4 SAS AF: 0.174

Gnomad4 FIN AF: 0.190

Gnomad4 NFE AF: 0.186

Gnomad4 OTH AF: 0.286

Alfa AF: 0.219 Hom.: 2951

Bravo AF: 0.282

Asia WGS AF: 0.238 AC: 830 AN: 3478

EpiCase AF: 0.194

EpiControl AF: 0.192

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.47
DANN	Benign	0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs13345; hg19: chr15-79224747; COSMIC: COSV54984668; COSMIC: COSV54984668;