rs17571

chr11-1761364-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A58E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.063 (350 hom., cov: 33)
  • Exomes 𝑓: 0.080 (4971 hom.)
• Consequence: CTSD NM_001909.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.354

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]

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

ACMG classification

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	UniProt
CTSD	NM_001909.5	c.173C>T	p.Ala58Val	missense_variant	2/9	ENST00000236671.7
PRADX	NR_182291.1	n.893G>A		non_coding_transcript_exon_variant	2/2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0629 AC: 9564 AN: 152140 Hom.: 347 Cov.: 33

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

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.: 32 AF XY: 0.0802 AC XY: 58300 AN XY: 726984

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.: 33 AF XY: 0.0612 AC XY: 4557 AN XY: 74450

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:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
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	Eurofins Ntd Llc (ga)	Jan 02, 2015	- -

Neuronal ceroid lipofuscinosis 10 Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Sep 15, 2017	- -
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, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 26, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -

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

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	9.7
Dann	Benign	0.82
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.24	N
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	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.26	T
Polyphen		0.18	.;.;B;.;.;.;.;.;.;.;.
Vest4		0.058
MPC		0.53
ClinPred		0.0019	T
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

Other links and lift over

dbSNP: rs17571; hg19: chr11-1782594; COSMIC: COSV52589252; COSMIC: COSV52589252;