rs11638844

Variant names:

• chr15-78939176-A-G
• rs11638844
• NM_004390.5:c.92-5T>C

Your query was ambiguous. Multiple possible variants found:

• chr15-78939176-A-G
• chr15-78939176-A-T

Variant summary

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

The NM_004390.5(CTSH):​c.92-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.645 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, intron
• Scores: Splicing: ADA: 0.00003227
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.199
• 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 -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 rank	MANE	Protein	UniProt
CTSH	NM_004390.5	c.92-5T>C		splice_region_variant, intron_variant	Intron 1 of 11	ENST00000220166.10	NP_004381.2
CTSH	NM_001411095.1	c.-23-5T>C		splice_region_variant, intron_variant	Intron 1 of 11		NP_001398024.1
CTSH	NM_001319137.2	c.-984-5T>C		splice_region_variant, intron_variant	Intron 1 of 12		NP_001306066.1
CTSH	XM_017021951.2	c.-101-5T>C		splice_region_variant, intron_variant	Intron 1 of 12		XP_016877440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSH	ENST00000220166.10	c.92-5T>C		splice_region_variant, intron_variant	Intron 1 of 11	1	NM_004390.5	ENSP00000220166.6

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

GnomAD2 exomes AF: 0.603 AC: 139403 AN: 231282 AF XY: 0.613

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 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

African (AFR) AF: 0.254 AC: 8167 AN: 32140

American (AMR) AF: 0.574 AC: 22430 AN: 39072

Ashkenazi Jewish (ASJ) AF: 0.673 AC: 17171 AN: 25528

East Asian (EAS) AF: 0.450 AC: 17588 AN: 39096

South Asian (SAS) AF: 0.643 AC: 51731 AN: 80504

European-Finnish (FIN) AF: 0.613 AC: 32591 AN: 53156

Middle Eastern (MID) AF: 0.630 AC: 3593 AN: 5702

European-Non Finnish (NFE) AF: 0.682 AC: 748973 AN: 1098366

Other (OTH) AF: 0.634 AC: 37504 AN: 59164

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

African (AFR) AF: 0.266 AC: 11017 AN: 41446

American (AMR) AF: 0.576 AC: 8795 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.664 AC: 2304 AN: 3468

East Asian (EAS) AF: 0.472 AC: 2430 AN: 5150

South Asian (SAS) AF: 0.630 AC: 3033 AN: 4818

European-Finnish (FIN) AF: 0.610 AC: 6355 AN: 10422

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.675 AC: 45789 AN: 67878

Other (OTH) AF: 0.547 AC: 1147 AN: 2098

Alfa AF: 0.615 Hom.: 21769

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
PhyloP100		-0.20
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11638844; hg19: chr15-79231518; COSMIC: COSV54984200; COSMIC: COSV54984200;