11-1753865-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001909.5(CTSD):c.1009G>A(p.Ala337Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000127 in 1,613,600 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A337S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00029 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 4 hom. )

Consequence

CTSD
NM_001909.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: -2.05

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

neuronal ceroid lipofuscinosis
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
neuronal ceroid lipofuscinosis 10
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Genomics England PanelApp

CTSD links:

ENSG00000250644 (HGNC:):

ENSG00000250644 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011360437).

BP6

Variant 11-1753865-C-T is Benign according to our data. Variant chr11-1753865-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 282729.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000289 (44/152266) while in subpopulation EAS AF = 0.00251 (13/5174). AF 95% confidence interval is 0.00149. There are 1 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001909.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSD	NM_001909.5	MANE Select	c.1009G>A	p.Ala337Thr	missense	Exon 8 of 9	NP_001900.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CTSD	ENST00000236671.7	TSL:1 MANE Select	c.1009G>A	p.Ala337Thr	missense	Exon 8 of 9	ENSP00000236671.2
ENSG00000250644	ENST00000636615.1	TSL:5	c.1009G>A	p.Ala337Thr	missense	Exon 8 of 10	ENSP00000490014.1
ENSG00000250644	ENST00000636397.1	TSL:5	c.1009G>A	p.Ala337Thr	missense	Exon 8 of 10	ENSP00000489910.1

Frequencies

GnomAD3 genomes

AF:

0.000283

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00251

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000232

AC:

AN:

250446

AF XY:

0.000170

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00267

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.000655

GnomAD4 exome

AF:

0.000110

AC:

161

AN:

1461334

Hom.:

Cov.:

AF XY:

0.0000908

AC XY:

AN XY:

726970

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33464

American (AMR)

AF:

0.00

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00126

AC:

AN:

39686

South Asian (SAS)

AF:

0.000104

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53318

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000989

AC:

AN:

1111694

Other (OTH)

AF:

0.00147

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.000289

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41546

American (AMR)

AF:

0.000784

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00251

AC:

AN:

5174

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67992

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000203

Hom.:

Bravo

AF:

0.000321

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000255

AC:

Asia WGS

AF:

0.00491

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CTSD: BP4

Aug 19, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 01, 2020

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

Neuronal ceroid lipofuscinosis 10

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Inborn genetic diseases

Benign:1

May 12, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.55

CADD

Benign

0.0030

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.20

Eigen

Benign

-2.5

Eigen_PC

Benign

-2.6

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.16

M_CAP

Benign

0.036

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.4

PhyloP100

-2.0

PrimateAI

Benign

0.19

PROVEAN

Benign

1.7

REVEL

Benign

0.069

Sift

Benign

0.59

Sift4G

Benign

0.58

Polyphen

0.0010

Vest4

0.11

MVP

0.085

MPC

0.48

ClinPred

0.0073

GERP RS

-7.8

PromoterAI

0.0030

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.059

gMVP

0.41

Mutation Taster

=100/0

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

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over