rs11555039

Variant names:

• chr11-1758975-A-G
• rs11555039
• NM_001909.5:c.465T>C

Your query was ambiguous. Multiple possible variants found:

• chr11-1758975-A-G
• chr11-1758975-A-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001909.5(CTSD):​c.465T>C​(p.Thr155Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.083 in 1,606,950 control chromosomes in the GnomAD database, including 5,929 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (560 hom., cov: 33)
  • Exomes 𝑓: 0.083 (5369 hom.)
• Consequence: CTSD NM_001909.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -4.36
• Publications: 15 publications found

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

ENSG00000250644 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.052).
• BP6: Variant 11-1758975-A-G is Benign according to our data. Variant chr11-1758975-A-G is described in ClinVar as Benign. ClinVar VariationId is 128876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.36 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0943 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSD	NM_001909.5	c.465T>C	p.Thr155Thr	synonymous_variant	Exon 4 of 9	ENST00000236671.7	NP_001900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSD	ENST00000236671.7	c.465T>C	p.Thr155Thr	synonymous_variant	Exon 4 of 9	1	NM_001909.5	ENSP00000236671.2
ENSG00000250644	ENST00000636615.1	c.465T>C	p.Thr155Thr	synonymous_variant	Exon 4 of 10	5		ENSP00000490014.1

Frequencies

GnomAD3 genomes AF: 0.0836 AC: 12719 AN: 152086 Hom.: 553 Cov.: 33

Gnomad AFR AF: 0.0967

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0812

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.0289

Gnomad SAS AF: 0.0924

Gnomad FIN AF: 0.0459

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.0848

Gnomad OTH AF: 0.0917

GnomAD2 exomes AF: 0.0770 AC: 19317 AN: 250942 AF XY: 0.0793

Gnomad AFR exome AF: 0.0984

Gnomad AMR exome AF: 0.0504

Gnomad ASJ exome AF: 0.109

Gnomad EAS exome AF: 0.0328

Gnomad FIN exome AF: 0.0526

Gnomad NFE exome AF: 0.0848

Gnomad OTH exome AF: 0.0929

GnomAD4 exome AF: 0.0830 AC: 120716 AN: 1454746 Hom.: 5369 Cov.: 30 AF XY: 0.0834 AC XY: 60429 AN XY: 724258

African (AFR) AF: 0.102 AC: 3391 AN: 33308

American (AMR) AF: 0.0521 AC: 2329 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 2715 AN: 26074

East Asian (EAS) AF: 0.0245 AC: 971 AN: 39666

South Asian (SAS) AF: 0.0976 AC: 8408 AN: 86108

European-Finnish (FIN) AF: 0.0514 AC: 2740 AN: 53344

Middle Eastern (MID) AF: 0.140 AC: 805 AN: 5756

European-Non Finnish (NFE) AF: 0.0851 AC: 94075 AN: 1105640

Other (OTH) AF: 0.0878 AC: 5282 AN: 60146

GnomAD4 genome AF: 0.0837 AC: 12736 AN: 152204 Hom.: 560 Cov.: 33 AF XY: 0.0809 AC XY: 6022 AN XY: 74420

African (AFR) AF: 0.0968 AC: 4020 AN: 41528

American (AMR) AF: 0.0811 AC: 1241 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 374 AN: 3472

East Asian (EAS) AF: 0.0288 AC: 149 AN: 5170

South Asian (SAS) AF: 0.0921 AC: 444 AN: 4822

European-Finnish (FIN) AF: 0.0459 AC: 487 AN: 10604

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.0848 AC: 5765 AN: 67996

Other (OTH) AF: 0.0935 AC: 197 AN: 2106

Alfa AF: 0.0864 Hom.: 363

Bravo AF: 0.0856

Asia WGS AF: 0.0910 AC: 314 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Jun 19, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuronal ceroid lipofuscinosis 10 Benign:3

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 01, 2017

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

May 07, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 15, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Inborn genetic diseases Benign:1

Mar 14, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.30
DANN	Benign	0.65
PhyloP100		-4.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11555039; hg19: chr11-1780205; COSMIC: COSV108036006; COSMIC: COSV108036006;