rs12148472

Variant names:

• chr15-78939136-T-C
• rs12148472
• NM_004390.5:c.123+4A>G

Your query was ambiguous. Multiple possible variants found:

• chr15-78939136-T-C
• chr15-78939136-T-G

Variant summary

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

The NM_004390.5(CTSH):​c.123+4A>G variant causes a splice 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: 𝑓 0.14 (1531 hom., cov: 33)
  • Exomes 𝑓: 0.13 (12129 hom.)
• Consequence: CTSH NM_004390.5 splice_region, intron
• Scores: Splicing: ADA: 0.2561
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.41
• Publications: 53 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=-0.49).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.176 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.123+4A>G		splice_region intron	N/A	NP_004381.2
	CTSH	NM_001411095.1		c.9+4A>G		splice_region intron	N/A	NP_001398024.1	E9PKT6
	CTSH	NM_001319137.2		c.-953+4A>G		splice_region intron	N/A	NP_001306066.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSH	ENST00000220166.10	TSL:1 MANE Select	c.123+4A>G		splice_region intron	N/A	ENSP00000220166.6	P09668
	CTSH	ENST00000615999.5	TSL:1	c.123+4A>G		splice_region intron	N/A	ENSP00000483303.2	A0A087X0D5
	CTSH	ENST00000527715.6	TSL:1	n.171+4A>G		splice_region intron	N/A

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

GnomAD2 exomes AF: 0.121 AC: 28483 AN: 235996 AF XY: 0.123

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 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

African (AFR) AF: 0.178 AC: 5775 AN: 32466

American (AMR) AF: 0.0768 AC: 3140 AN: 40886

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 2690 AN: 25870

East Asian (EAS) AF: 0.0622 AC: 2459 AN: 39548

South Asian (SAS) AF: 0.144 AC: 11760 AN: 81796

European-Finnish (FIN) AF: 0.138 AC: 7376 AN: 53318

Middle Eastern (MID) AF: 0.0934 AC: 536 AN: 5738

European-Non Finnish (NFE) AF: 0.128 AC: 141297 AN: 1105150

Other (OTH) AF: 0.127 AC: 7622 AN: 59808

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

African (AFR) AF: 0.180 AC: 7455 AN: 41444

American (AMR) AF: 0.0916 AC: 1396 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 370 AN: 3472

East Asian (EAS) AF: 0.0616 AC: 319 AN: 5176

South Asian (SAS) AF: 0.149 AC: 715 AN: 4804

European-Finnish (FIN) AF: 0.132 AC: 1386 AN: 10528

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.129 AC: 8773 AN: 67992

Other (OTH) AF: 0.131 AC: 277 AN: 2108

Alfa AF: 0.127 Hom.: 4862

Bravo AF: 0.133

Asia WGS AF: 0.111 AC: 386 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	17
DANN	Benign	0.84
PhyloP100		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=85/15	polymorphism (auto)

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

Other links and lift over

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