11-1753527-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001909.5(CTSD):c.1215C>A(p.Gly405=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.017 in 1,612,964 control chromosomes in the GnomAD database, including 292 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (27 hom., cov: 33)
  • Exomes 𝑓: 0.017 (265 hom.)
• Consequence: CTSD NM_001909.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.22

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 11-1753527-G-T is Benign according to our data. Variant chr11-1753527-G-T is described in ClinVar as [Benign]. Clinvar id is 128872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-1753527-G-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.22 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0124 (1883/152262) while in subpopulation NFE AF= 0.0202 (1376/67996). AF 95% confidence interval is 0.0193. There are 27 homozygotes in gnomad4. There are 837 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSD	NM_001909.5	c.1215C>A	p.Gly405=	synonymous_variant	9/9	ENST00000236671.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSD	ENST00000236671.7	c.1215C>A	p.Gly405=	synonymous_variant	9/9	1	NM_001909.5	P2

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1885 AN: 152144 Hom.: 27 Cov.: 33

Gnomad AFR AF: 0.00403

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00903

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00885

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0202

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.0117 AC: 2930 AN: 249950 Hom.: 32 AF XY: 0.0120 AC XY: 1630 AN XY: 135608

Gnomad AFR exome AF: 0.00310

Gnomad AMR exome AF: 0.00489

Gnomad ASJ exome AF: 0.0123

Gnomad EAS exome AF: 0.0000548

Gnomad SAS exome AF: 0.00274

Gnomad FIN exome AF: 0.0114

Gnomad NFE exome AF: 0.0196

Gnomad OTH exome AF: 0.00835

GnomAD4 exome AF: 0.0175 AC: 25519 AN: 1460702 Hom.: 265 Cov.: 33 AF XY: 0.0171 AC XY: 12450 AN XY: 726688

Gnomad4 AFR exome AF: 0.00314

Gnomad4 AMR exome AF: 0.00539

Gnomad4 ASJ exome AF: 0.0126

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00272

Gnomad4 FIN exome AF: 0.0114

Gnomad4 NFE exome AF: 0.0207

Gnomad4 OTH exome AF: 0.0140

GnomAD4 genome AF: 0.0124 AC: 1883 AN: 152262 Hom.: 27 Cov.: 33 AF XY: 0.0112 AC XY: 837 AN XY: 74454

Gnomad4 AFR AF: 0.00402

Gnomad4 AMR AF: 0.00901

Gnomad4 ASJ AF: 0.0147

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00885

Gnomad4 NFE AF: 0.0202

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0143 Hom.: 11

Bravo AF: 0.0123

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Neuronal ceroid lipofuscinosis 10 Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 09, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jul 20, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 25, 2017	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 15, 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

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
Cadd	Benign	4.4
Dann	Benign	0.90
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

Other links and lift over

dbSNP: rs138733377; hg19: chr11-1774757;