rs757712173

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_001909.5(CTSD):c.8C>T(p.Pro3Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000769 in 1,524,814 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00078 ( 1 hom. )

Consequence

CTSD
NM_001909.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6B:3

Conservation

PhyloP100: -0.399

Variant links:

Genes affected

CTSD (HGNC:2529): (cathepsin D) This gene encodes a member of the A1 family of peptidases. The encoded preproprotein is proteolytically processed to generate multiple protein products. These products include the cathepsin D light and heavy chains, which heterodimerize to form the mature enzyme. This enzyme exhibits pepsin-like activity and plays a role in protein turnover and in the proteolytic activation of hormones and growth factors. Mutations in this gene play a causal role in neuronal ceroid lipofuscinosis-10 and may be involved in the pathogenesis of several other diseases, including breast cancer and possibly Alzheimer's disease. [provided by RefSeq, Nov 2015]

CTSD links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.016937643).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000663 (101/152308) while in subpopulation NFE AF= 0.00125 (85/68014). AF 95% confidence interval is 0.00104. There are 0 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTSD	NM_001909.5 linkuse as main transcript	c.8C>T	p.Pro3Leu	missense_variant	1/9	ENST00000236671.7	NP_001900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSD	ENST00000236671.7 linkuse as main transcript	c.8C>T	p.Pro3Leu	missense_variant	1/9	1	NM_001909.5	ENSP00000236671	P2

Frequencies

GnomAD3 genomes

AF:

0.000664

AC:

101

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00125

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000538

AC:

AN:

120710

Hom.:

AF XY:

0.000467

AC XY:

AN XY:

66318

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000863

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000527

Gnomad FIN exome

AF:

0.00109

Gnomad NFE exome

AF:

0.000923

Gnomad OTH exome

AF:

0.000536

GnomAD4 exome

AF:

0.000781

AC:

1072

AN:

1372506

Hom.:

Cov.:

AF XY:

0.000824

AC XY:

558

AN XY:

677286

show subpopulations

Gnomad4 AFR exome

AF:

0.0000688

Gnomad4 AMR exome

AF:

0.0000861

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000438

Gnomad4 FIN exome

AF:

0.000994

Gnomad4 NFE exome

AF:

0.000893

Gnomad4 OTH exome

AF:

0.000647

GnomAD4 genome

AF:

0.000663

AC:

101

AN:

152308

Hom.:

Cov.:

AF XY:

0.000537

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.000660

Gnomad4 NFE

AF:

0.00125

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00139

Hom.:

Bravo

AF:

0.000393

ExAC

AF:

0.000579

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 02, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 10, 2018	The P3L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P3L variant is not observed at a significant frequency in large population cohorts; however, limited data are available (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P3L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Neuronal ceroid lipofuscinosis 10

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 09, 2021	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 06, 2023

The c.8C>T (p.P3L) alteration is located in exon 1 (coding exon 1) of the CTSD gene. This alteration results from a C to T substitution at nucleotide position 8, causing the proline (P) at amino acid position 3 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Neuronal ceroid lipofuscinosis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 25, 2022

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 3 of the CTSD protein (p.Pro3Leu). This variant is present in population databases (rs757712173, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with CTSD-related conditions. ClinVar contains an entry for this variant (Variation ID: 205353). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

CTSD-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 05, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.26

.;.;T;T;.;T;.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.55

T;T;T;T;T;T;T;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.017

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.63

.;.;N;.;.;.;.;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.020

.;.;N;.;.;.;.;.

REVEL

Benign

0.048

Sift

Benign

0.68

.;.;T;.;.;.;.;.

Sift4G

Benign

0.44

.;.;T;.;.;.;.;.

Polyphen

0.0

.;.;B;.;.;.;.;.

Vest4

0.14

MVP

0.35

MPC

0.51

ClinPred

0.012

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.042

gMVP

0.37

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over