11-1753293-G-C

Position:

• chr11-1753293-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001909.5(CTSD):​c.*210C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 633,340 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (3 hom.)
• Consequence: CTSD NM_001909.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.544

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00166 (247/148836) while in subpopulation AMR AF= 0.00254 (38/14984). AF 95% confidence interval is 0.0019. There are 0 homozygotes in gnomad4. There are 116 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSD	NM_001909.5	c.*210C>G		3_prime_UTR_variant	9/9	ENST00000236671.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSD	ENST00000236671.7	c.*210C>G		3_prime_UTR_variant	9/9	1	NM_001909.5	P2

Frequencies

GnomAD3 genomes AF: 0.00166 AC: 247 AN: 148716 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00254

Gnomad ASJ AF: 0.0177

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000201

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00185

Gnomad OTH AF: 0.00394

GnomAD4 exome AF: 0.00201 AC: 975 AN: 484504 Hom.: 3 Cov.: 5 AF XY: 0.00207 AC XY: 535 AN XY: 257900

Gnomad4 AFR exome AF: 0.000146

Gnomad4 AMR exome AF: 0.00142

Gnomad4 ASJ exome AF: 0.0149

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00239

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00173

Gnomad4 OTH exome AF: 0.00237

GnomAD4 genome AF: 0.00166 AC: 247 AN: 148836 Hom.: 0 Cov.: 33 AF XY: 0.00159 AC XY: 116 AN XY: 72750

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.00254

Gnomad4 ASJ AF: 0.0177

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.000201

Gnomad4 NFE AF: 0.00185

Gnomad4 OTH AF: 0.00390

Alfa AF: 0.00166 Hom.: 0

Bravo AF: 0.00144

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neuronal ceroid lipofuscinosis 10 Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.1
DANN	Benign	0.71
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: rs528911846; hg19: chr11-1774523;