rs78306946

Positions:

chr11-1754015-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001909.5(CTSD):c.951C>T(p.Ala317Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00248 in 1,479,412 control chromosomes in the GnomAD database, including 120 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0030 ( 17 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 103 hom. )

Consequence

CTSD
NM_001909.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -2.01

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 links:

ENSG00000250644 (HGNC:):

ENSG00000250644 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 11-1754015-G-A is Benign according to our data. Variant chr11-1754015-G-A is described in ClinVar as [Benign]. Clinvar id is 137041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.01 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0807 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTSD	NM_001909.5 link	c.951C>T	p.Ala317Ala	synonymous_variant	7/9	ENST00000236671.7	NP_001900.1	P07339V9HWI3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSD	ENST00000236671.7 link	c.951C>T	p.Ala317Ala	synonymous_variant	7/9	1	NM_001909.5	ENSP00000236671.2		P07339
ENSG00000250644	ENST00000636615.1 link	c.951C>T	p.Ala317Ala	synonymous_variant	7/10	5		ENSP00000490014.1		A0A1B0GU92

Frequencies

GnomAD3 genomes

AF:

0.00304

AC:

444

AN:

145918

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000745

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000816

Gnomad ASJ

AF:

0.000293

Gnomad EAS

AF:

0.0881

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00169

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000151

Gnomad OTH

AF:

0.00292

GnomAD3 exomes

AF:

0.00595

AC:

1408

AN:

236662

Hom.:

AF XY:

0.00553

AC XY:

714

AN XY:

129088

show subpopulations

Gnomad AFR exome

AF:

0.000134

Gnomad AMR exome

AF:

0.0000596

Gnomad ASJ exome

AF:

0.000308

Gnomad EAS exome

AF:

0.0737

Gnomad SAS exome

AF:

0.000871

Gnomad FIN exome

AF:

0.00204

Gnomad NFE exome

AF:

0.000236

Gnomad OTH exome

AF:

0.00206

GnomAD4 exome

AF:

0.00242

AC:

3225

AN:

1333346

Hom.:

103

Cov.:

AF XY:

0.00235

AC XY:

1557

AN XY:

662400

show subpopulations

Gnomad4 AFR exome

AF:

0.0000677

Gnomad4 AMR exome

AF:

0.0000497

Gnomad4 ASJ exome

AF:

0.000236

Gnomad4 EAS exome

AF:

0.0863

Gnomad4 SAS exome

AF:

0.000922

Gnomad4 FIN exome

AF:

0.00266

Gnomad4 NFE exome

AF:

0.000112

Gnomad4 OTH exome

AF:

0.00448

GnomAD4 genome

AF:

0.00303

AC:

442

AN:

146066

Hom.:

Cov.:

AF XY:

0.00344

AC XY:

245

AN XY:

71268

show subpopulations

Gnomad4 AFR

AF:

0.0000743

Gnomad4 AMR

AF:

0.000815

Gnomad4 ASJ

AF:

0.000293

Gnomad4 EAS

AF:

0.0879

Gnomad4 SAS

AF:

0.000986

Gnomad4 FIN

AF:

0.00169

Gnomad4 NFE

AF:

0.000151

Gnomad4 OTH

AF:

0.00289

Alfa

AF:

0.000508

Hom.:

Bravo

AF:

0.00256

Asia WGS

AF:

0.0260

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 28, 2017	- -

Neuronal ceroid lipofuscinosis 10

Benign:1

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. -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 01, 2017

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

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.084

DANN

Benign

0.79

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over