rs121912789

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_001909.5(CTSD):c.685T>A(p.Phe229Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CTSD
NM_001909.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 8.38

Publications

12 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: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 11-1757343-A-T is Pathogenic according to our data. Variant chr11-1757343-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 17573.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSD	NM_001909.5 link	c.685T>A	p.Phe229Ile	missense_variant	Exon 5 of 9	ENST00000236671.7	NP_001900.1	P07339V9HWI3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSD	ENST00000236671.7 link	c.685T>A	p.Phe229Ile	missense_variant	Exon 5 of 9	1	NM_001909.5	ENSP00000236671.2		P07339
ENSG00000250644	ENST00000636615.1 link	c.685T>A	p.Phe229Ile	missense_variant	Exon 5 of 10	5		ENSP00000490014.1		A0A1B0GU92

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461590

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727108

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53206

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111946

Other (OTH)

AF:

0.00

AC:

AN:

60390

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

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41474

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2094

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

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:

0.0000712

Hom.:

Bravo

AF:

0.00000756

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis 10

Pathogenic:1

Jun 01, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.75

.;.;D;T;.;T;.;T;.;.

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.56

MutationAssessor

Pathogenic

3.8

.;.;H;.;.;.;.;.;.;.

PhyloP100

8.4

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-5.8

.;.;D;.;.;.;.;.;D;D

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

.;.;D;.;.;.;.;.;D;D

Sift4G

Pathogenic

0.0010

.;.;D;.;.;.;.;.;D;.

Polyphen

1.0

.;.;D;.;.;.;.;.;.;.

Vest4

0.96

MutPred

0.98

Loss of catalytic residue at F229 (P = 0.0688);Loss of catalytic residue at F229 (P = 0.0688);Loss of catalytic residue at F229 (P = 0.0688);Loss of catalytic residue at F229 (P = 0.0688);Loss of catalytic residue at F229 (P = 0.0688);.;Loss of catalytic residue at F229 (P = 0.0688);.;.;.;

MVP

0.73

MPC

1.7

ClinPred

1.0

GERP RS

4.1

PromoterAI

0.025

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.98

gMVP

0.97

Mutation Taster

=18/82

disease causing (ClinVar)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over