Genetic Variant CTSH:n.3585G>A (chr15-78921873-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000527715.6(CTSH):n.3585G>A variant causes a non coding transcript exon 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
ENST00000527715.6 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.806

Publications

21 publications found

Variant links:

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]

CTSH links:

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ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CTSH	NM_004390.5 link	c.*257G>A	3_prime_UTR_variant	Exon 12 of 12	ENST00000220166.10	NP_004381.2	P09668
CTSH	NM_001411095.1 link	c.*257G>A	3_prime_UTR_variant	Exon 12 of 12		NP_001398024.1
CTSH	NM_001319137.2 link	c.*257G>A	3_prime_UTR_variant	Exon 13 of 13		NP_001306066.1
CTSH	XM_017021951.2 link	c.*257G>A	3_prime_UTR_variant	Exon 13 of 13		XP_016877440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSH	ENST00000220166.10 link	c.*257G>A		3_prime_UTR_variant	Exon 12 of 12	1	NM_004390.5	ENSP00000220166.6		P09668

Frequencies

GnomAD3 genomes

AF:

0.215

AC:

32754

AN:

152066

Hom.:

3995

Cov.:

show subpopulations

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.:

AF XY:

0.236

AC XY:

44205

AN XY:

186986

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

2961

5921

8882

11842

14803

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

270

540

810

1080

1350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.215

AC:

32759

AN:

152184

Hom.:

3996

Cov.:

AF XY:

0.217

AC XY:

16124

AN XY:

74394

show subpopulations

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.269

AC:

18315

AN:

67994

Other (OTH)

AF:

0.208

AC:

439

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1304

2608

3912

5216

6520

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

350

700

1050

1400

1750

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

2.5

(source)

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)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over