11-1753203-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001909.5(CTSD):c.*300G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00572 in 462,604 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (49 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (12 hom.)
• Consequence: CTSD NM_001909.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.282

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 11-1753203-C-T is Benign according to our data. Variant chr11-1753203-C-T is described in ClinVar as [Benign]. Clinvar id is 303828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.014 (2131/152282) while in subpopulation AFR AF= 0.0486 (2020/41562). AF 95% confidence interval is 0.0468. There are 49 homozygotes in gnomad4. There are 1026 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 49 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSD	NM_001909.5	c.*300G>A		3_prime_UTR_variant	9/9	ENST00000236671.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSD	ENST00000236671.7	c.*300G>A		3_prime_UTR_variant	9/9	1	NM_001909.5	P2

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2128 AN: 152164 Hom.: 49 Cov.: 33

Gnomad AFR AF: 0.0487

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00814

GnomAD4 exome AF: 0.00167 AC: 517 AN: 310322 Hom.: 12 Cov.: 0 AF XY: 0.00138 AC XY: 228 AN XY: 165250

Gnomad4 AFR exome AF: 0.0449

Gnomad4 AMR exome AF: 0.00261

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000551

Gnomad4 SAS exome AF: 0.000412

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000330

Gnomad4 OTH exome AF: 0.00272

GnomAD4 genome AF: 0.0140 AC: 2131 AN: 152282 Hom.: 49 Cov.: 33 AF XY: 0.0138 AC XY: 1026 AN XY: 74448

Gnomad4 AFR AF: 0.0486

Gnomad4 AMR AF: 0.00529

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00806

Alfa AF: 0.00151 Hom.: 0

Bravo AF: 0.0160

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 07, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	5.1
Dann	Benign	0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs113940256; hg19: chr11-1774433;