rs11555039

Positions:

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

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong 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

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]

ENSG00000250644 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 11-1758975-A-G is Benign according to our data. Variant chr11-1758975-A-G is described in ClinVar as [Benign]. Clinvar id is 128876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-1758975-A-G is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
CTSD	NM_001909.5	c.465T>C	p.Thr155Thr	synonymous_variant	4/9	ENST00000236671.7	NP_001900.1

Ensembl

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

GnomAD3 exomes AF: 0.0770 AC: 19317 AN: 250942 Hom.: 821 AF XY: 0.0793 AC XY: 10764 AN XY: 135698

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 SAS exome AF: 0.0970

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

Gnomad4 AFR exome AF: 0.102

Gnomad4 AMR exome AF: 0.0521

Gnomad4 ASJ exome AF: 0.104

Gnomad4 EAS exome AF: 0.0245

Gnomad4 SAS exome AF: 0.0976

Gnomad4 FIN exome AF: 0.0514

Gnomad4 NFE exome AF: 0.0851

Gnomad4 OTH exome AF: 0.0878

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

Gnomad4 AFR AF: 0.0968

Gnomad4 AMR AF: 0.0811

Gnomad4 ASJ AF: 0.108

Gnomad4 EAS AF: 0.0288

Gnomad4 SAS AF: 0.0921

Gnomad4 FIN AF: 0.0459

Gnomad4 NFE AF: 0.0848

Gnomad4 OTH AF: 0.0935

Alfa AF: 0.0864 Hom.: 312

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

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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 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. -

Neuronal ceroid lipofuscinosis 10 Benign:3

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Sep 01, 2017	- -
Benign, 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 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. -

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	Dec 15, 2015	- -
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

Mar 14, 2016

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
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.30
DANN	Benign	0.65

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

Other links and lift over

dbSNP: rs11555039; hg19: chr11-1780205;