Genetic Variant CTSH:p.Leu7Pro (chr15-78944962-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004390.5(CTSH):c.20T>C(p.Leu7Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,084 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CTSH
NM_004390.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.00600

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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSH	NM_004390.5 link	c.20T>C	p.Leu7Pro	missense_variant	Exon 1 of 12	ENST00000220166.10	NP_004381.2	P09668
CTSH	NM_001411095.1 link	c.-208T>C		5_prime_UTR_variant	Exon 1 of 12		NP_001398024.1
CTSH	NM_001319137.2 link	c.-1056T>C		5_prime_UTR_variant	Exon 1 of 13		NP_001306066.1
CTSH	XM_017021951.2 link	c.-173T>C		5_prime_UTR_variant	Exon 1 of 13		XP_016877440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSH	ENST00000220166.10 link	c.20T>C	p.Leu7Pro	missense_variant	Exon 1 of 12	1	NM_004390.5	ENSP00000220166.6		P09668

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1393214

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

687274

African (AFR)

AF:

0.00

AC:

AN:

31266

American (AMR)

AF:

0.00

AC:

AN:

35434

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25090

East Asian (EAS)

AF:

0.00

AC:

AN:

35418

South Asian (SAS)

AF:

0.00

AC:

AN:

78764

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46504

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5604

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1077300

Other (OTH)

AF:

0.00

AC:

AN:

57834

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152084

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41390

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 23, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.20T>C (p.L7P) alteration is located in exon 1 (coding exon 1) of the CTSH gene. This alteration results from a T to C substitution at nucleotide position 20, causing the leucine (L) at amino acid position 7 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.28

T;.

Eigen

Benign

0.050

Eigen_PC

Benign

-0.046

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.63

T;T

M_CAP

Pathogenic

0.87

MetaRNN

Uncertain

0.69

D;D

MetaSVM

Benign

-0.46

MutationAssessor

Benign

0.97

L;.

PhyloP100

0.0060

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.8

D;.

REVEL

Uncertain

0.57

Sift

Uncertain

0.0020

D;.

Sift4G

Uncertain

0.0080

D;T

Vest4

0.40

MutPred

0.71

Gain of disorder (P = 0.0124);Gain of disorder (P = 0.0124);

MVP

0.65

MPC

0.71

ClinPred

0.75

GERP RS

3.0

PromoterAI

-0.028

Neutral

(source)

Varity_R

0.67

gMVP

0.83

Mutation Taster

=70/30

polymorphism

(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

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over