15-78921873-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004390.5(CTSH):​c.*257G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 512,182 control chromosomes in the GnomAD database, including 15,307 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 0.22 (3996 hom., cov: 32)
  • Exomes 𝑓: 0.24 (11311 hom.)
• Consequence: CTSH NM_004390.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.806
• Publications: 21 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

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

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32754 AN: 152066 Hom.: 3995 Cov.: 32

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.0389

Gnomad SAS AF: 0.202

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.210

GnomAD4 exome AF: 0.237 AC: 85399 AN: 359998 Hom.: 11311 Cov.: 0 AF XY: 0.236 AC XY: 44205 AN XY: 186986

African (AFR) AF: 0.120 AC: 1255 AN: 10450

American (AMR) AF: 0.221 AC: 3168 AN: 14356

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 2232 AN: 11672

East Asian (EAS) AF: 0.0516 AC: 1312 AN: 25418

South Asian (SAS) AF: 0.198 AC: 6288 AN: 31752

European-Finnish (FIN) AF: 0.350 AC: 8531 AN: 24376

Middle Eastern (MID) AF: 0.162 AC: 269 AN: 1660

European-Non Finnish (NFE) AF: 0.263 AC: 57418 AN: 218630

Other (OTH) AF: 0.227 AC: 4926 AN: 21684

GnomAD4 genome AF: 0.215 AC: 32759 AN: 152184 Hom.: 3996 Cov.: 32 AF XY: 0.217 AC XY: 16124 AN XY: 74394

African (AFR) AF: 0.121 AC: 5011 AN: 41518

American (AMR) AF: 0.216 AC: 3305 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 698 AN: 3472

East Asian (EAS) AF: 0.0388 AC: 201 AN: 5182

South Asian (SAS) AF: 0.202 AC: 974 AN: 4830

European-Finnish (FIN) AF: 0.338 AC: 3580 AN: 10588

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.269 AC: 18315 AN: 67994

Other (OTH) AF: 0.208 AC: 439 AN: 2114

Alfa AF: 0.231 Hom.: 2824

Bravo AF: 0.198

Asia WGS AF: 0.122 AC: 428 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.5
DANN	Benign	0.75
PhyloP100		-0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs3129; hg19: chr15-79214215;