rs13345

Variant names:

• chr15-78932405-C-T
• rs13345
• NM_004390.5:c.459G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_004390.5(CTSH):​c.459G>A​(p.Ala153Ala) 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
• Publications: 20 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: Benign. The variant received -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 rank	MANE	Protein	UniProt
CTSH	NM_004390.5	c.459G>A	p.Ala153Ala	synonymous_variant	Exon 6 of 12	ENST00000220166.10	NP_004381.2
CTSH	NM_001411095.1	c.345G>A	p.Ala115Ala	synonymous_variant	Exon 6 of 12		NP_001398024.1
CTSH	XM_017021951.2	c.405G>A	p.Ala135Ala	synonymous_variant	Exon 7 of 13		XP_016877440.1
CTSH	NM_001319137.2	c.-479G>A		5_prime_UTR_variant	Exon 7 of 13		NP_001306066.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSH	ENST00000220166.10	c.459G>A	p.Ala153Ala	synonymous_variant	Exon 6 of 12	1	NM_004390.5	ENSP00000220166.6

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

GnomAD2 exomes AF: 0.215 AC: 54046 AN: 251280 AF XY: 0.210

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 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

African (AFR) AF: 0.459 AC: 15370 AN: 33472

American (AMR) AF: 0.194 AC: 8674 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 5490 AN: 26134

East Asian (EAS) AF: 0.331 AC: 13151 AN: 39688

South Asian (SAS) AF: 0.166 AC: 14318 AN: 86248

European-Finnish (FIN) AF: 0.190 AC: 10144 AN: 53398

Middle Eastern (MID) AF: 0.253 AC: 1462 AN: 5768

European-Non Finnish (NFE) AF: 0.182 AC: 202516 AN: 1111620

Other (OTH) AF: 0.211 AC: 12752 AN: 60370

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

African (AFR) AF: 0.445 AC: 18439 AN: 41430

American (AMR) AF: 0.240 AC: 3670 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 761 AN: 3470

East Asian (EAS) AF: 0.319 AC: 1643 AN: 5152

South Asian (SAS) AF: 0.174 AC: 839 AN: 4824

European-Finnish (FIN) AF: 0.190 AC: 2002 AN: 10564

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.186 AC: 12662 AN: 67960

Other (OTH) AF: 0.286 AC: 604 AN: 2114

Alfa AF: 0.217 Hom.: 3763

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
AlphaMissense	Benign	0.15
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.47
DANN	Benign	0.62
PhyloP100		-7.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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