rs17571

Positions:

chr11-1761364-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001909.5(CTSD):c.173C>T(p.Ala58Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.078 in 1,613,604 control chromosomes in the GnomAD database, including 5,321 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.063 ( 350 hom., cov: 33)

Exomes 𝑓: 0.080 ( 4971 hom. )

Consequence

CTSD
NM_001909.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.354

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:

PRADX (HGNC:40168): (PRC2 and DDX5 associated lncRNA)

PRADX links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018743575).

BP6

Variant 11-1761364-G-A is Benign according to our data. Variant chr11-1761364-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 128873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-1761364-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0825 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTSD	NM_001909.5 linkuse as main transcript	c.173C>T	p.Ala58Val	missense_variant	2/9	ENST00000236671.7	NP_001900.1
PRADX	NR_182291.1 linkuse as main transcript	n.893G>A		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSD	ENST00000236671.7 linkuse as main transcript	c.173C>T	p.Ala58Val	missense_variant	2/9	1	NM_001909.5	ENSP00000236671	P2
PRADX	ENST00000449248.1 linkuse as main transcript	n.893G>A		non_coding_transcript_exon_variant	2/2	1

Frequencies

GnomAD3 genomes

AF:

0.0629

AC:

9564

AN:

152140

Hom.:

347

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0298

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.0720

Gnomad ASJ

AF:

0.0905

Gnomad EAS

AF:

0.0285

Gnomad SAS

AF:

0.0898

Gnomad FIN

AF:

0.0461

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.0826

Gnomad OTH

AF:

0.0780

GnomAD3 exomes

AF:

0.0699

AC:

17549

AN:

250886

Hom.:

697

AF XY:

0.0737

AC XY:

10013

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.0276

Gnomad AMR exome

AF:

0.0462

Gnomad ASJ exome

AF:

0.0948

Gnomad EAS exome

AF:

0.0327

Gnomad SAS exome

AF:

0.0949

Gnomad FIN exome

AF:

0.0526

Gnomad NFE exome

AF:

0.0827

Gnomad OTH exome

AF:

0.0868

GnomAD4 exome

AF:

0.0796

AC:

116346

AN:

1461346

Hom.:

4971

Cov.:

AF XY:

0.0802

AC XY:

58300

AN XY:

726984

show subpopulations

Gnomad4 AFR exome

AF:

0.0290

Gnomad4 AMR exome

AF:

0.0473

Gnomad4 ASJ exome

AF:

0.0883

Gnomad4 EAS exome

AF:

0.0245

Gnomad4 SAS exome

AF:

0.0951

Gnomad4 FIN exome

AF:

0.0514

Gnomad4 NFE exome

AF:

0.0840

Gnomad4 OTH exome

AF:

0.0809

GnomAD4 genome

AF:

0.0628

AC:

9566

AN:

152258

Hom.:

350

Cov.:

AF XY:

0.0612

AC XY:

4557

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0298

Gnomad4 AMR

AF:

0.0719

Gnomad4 ASJ

AF:

0.0905

Gnomad4 EAS

AF:

0.0284

Gnomad4 SAS

AF:

0.0894

Gnomad4 FIN

AF:

0.0461

Gnomad4 NFE

AF:

0.0827

Gnomad4 OTH

AF:

0.0791

Alfa

AF:

0.0799

Hom.:

1077

Bravo

AF:

0.0618

TwinsUK

AF:

0.0777

AC:

288

ALSPAC

AF:

0.0791

AC:

305

ESP6500AA

AF:

0.0318

AC:

140

ESP6500EA

AF:

0.0811

AC:

697

ExAC

AF:

0.0702

AC:

8517

Asia WGS

AF:

0.0820

AC:

285

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 08, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 02, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Neuronal ceroid lipofuscinosis 10

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Sep 15, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 26, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Neuronal ceroid lipofuscinosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.54

CADD

Benign

9.7

DANN

Benign

0.82

DEOGEN2

Benign

0.35

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

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.70

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

MetaRNN

Benign

0.0019

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

.;.;L;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.2

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

REVEL

Benign

0.11

Sift

Benign

0.66

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

Sift4G

Benign

0.31

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

Polyphen

0.18

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

Vest4

0.058

MPC

0.53

ClinPred

0.0019

GERP RS

-1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.019

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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