11-1752906-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001909.5(CTSD):c.*597A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 164,580 control chromosomes in the GnomAD database, including 2,025 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.15 (1872 hom., cov: 33)
  • Exomes 𝑓: 0.13 (153 hom.)
• Consequence: CTSD NM_001909.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.29

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 11-1752906-T-G is Benign according to our data. Variant chr11-1752906-T-G is described in ClinVar as [Benign]. Clinvar id is 303822.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.265 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSD	NM_001909.5	c.*597A>C		3_prime_UTR_variant	9/9	ENST00000236671.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSD	ENST00000236671.7	c.*597A>C		3_prime_UTR_variant	9/9	1	NM_001909.5	P2

Frequencies

GnomAD3 genomes AF: 0.151 AC: 23012 AN: 152150 Hom.: 1868 Cov.: 33

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.280

Gnomad EAS AF: 0.100

Gnomad SAS AF: 0.277

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.175

GnomAD4 exome AF: 0.130 AC: 1598 AN: 12312 Hom.: 153 Cov.: 0 AF XY: 0.139 AC XY: 895 AN XY: 6430

Gnomad4 AFR exome AF: 0.125

Gnomad4 AMR exome AF: 0.0818

Gnomad4 ASJ exome AF: 0.183

Gnomad4 EAS exome AF: 0.0619

Gnomad4 SAS exome AF: 0.233

Gnomad4 FIN exome AF: 0.0599

Gnomad4 NFE exome AF: 0.122

Gnomad4 OTH exome AF: 0.133

GnomAD4 genome AF: 0.151 AC: 23031 AN: 152268 Hom.: 1872 Cov.: 33 AF XY: 0.150 AC XY: 11165 AN XY: 74470

Gnomad4 AFR AF: 0.132

Gnomad4 AMR AF: 0.129

Gnomad4 ASJ AF: 0.280

Gnomad4 EAS AF: 0.100

Gnomad4 SAS AF: 0.277

Gnomad4 FIN AF: 0.107

Gnomad4 NFE AF: 0.163

Gnomad4 OTH AF: 0.175

Alfa AF: 0.154 Hom.: 316

Bravo AF: 0.151

Asia WGS AF: 0.180 AC: 626 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
Cadd	Benign	0.61
Dann	Benign	0.39

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: rs8839; hg19: chr11-1774136;