rs78735768

Positions:

• chr11-1754155-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001909.5(CTSD):​c.828-17G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.069 in 1,604,836 control chromosomes in the GnomAD database, including 4,220 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (272 hom., cov: 33)
  • Exomes 𝑓: 0.070 (3948 hom.)
• Consequence: CTSD NM_001909.5 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.09

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 (MetaRNN=0.0028076768).
• BP6: Variant 11-1754155-C-T is Benign according to our data. Variant chr11-1754155-C-T is described in ClinVar as [Benign]. Clinvar id is 258490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-1754155-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0814 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTSD	NM_001909.5	c.828-17G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000236671.7	NP_001900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSD	ENST00000236671.7	c.828-17G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001909.5	ENSP00000236671	P2

Frequencies

GnomAD3 genomes AF: 0.0550 AC: 8372 AN: 152104 Hom.: 271 Cov.: 33

Gnomad AFR AF: 0.0246

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0614

Gnomad ASJ AF: 0.0902

Gnomad EAS AF: 0.0291

Gnomad SAS AF: 0.0886

Gnomad FIN AF: 0.0422

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0716

Gnomad OTH AF: 0.0708

GnomAD3 exomes AF: 0.0636 AC: 14967 AN: 235162 Hom.: 546 AF XY: 0.0674 AC XY: 8686 AN XY: 128944

Gnomad AFR exome AF: 0.0240

Gnomad AMR exome AF: 0.0422

Gnomad ASJ exome AF: 0.0957

Gnomad EAS exome AF: 0.0340

Gnomad SAS exome AF: 0.0934

Gnomad FIN exome AF: 0.0462

Gnomad NFE exome AF: 0.0714

Gnomad OTH exome AF: 0.0788

GnomAD4 exome AF: 0.0705 AC: 102338 AN: 1452614 Hom.: 3948 Cov.: 37 AF XY: 0.0714 AC XY: 51633 AN XY: 722702

Gnomad4 AFR exome AF: 0.0233

Gnomad4 AMR exome AF: 0.0436

Gnomad4 ASJ exome AF: 0.0890

Gnomad4 EAS exome AF: 0.0257

Gnomad4 SAS exome AF: 0.0936

Gnomad4 FIN exome AF: 0.0464

Gnomad4 NFE exome AF: 0.0730

Gnomad4 OTH exome AF: 0.0729

GnomAD4 genome AF: 0.0550 AC: 8367 AN: 152222 Hom.: 272 Cov.: 33 AF XY: 0.0539 AC XY: 4007 AN XY: 74400

Gnomad4 AFR AF: 0.0245

Gnomad4 AMR AF: 0.0613

Gnomad4 ASJ AF: 0.0902

Gnomad4 EAS AF: 0.0288

Gnomad4 SAS AF: 0.0883

Gnomad4 FIN AF: 0.0422

Gnomad4 NFE AF: 0.0716

Gnomad4 OTH AF: 0.0720

Alfa AF: 0.0708 Hom.: 131

Bravo AF: 0.0540

TwinsUK AF: 0.0693 AC: 257

ALSPAC AF: 0.0729 AC: 281

ESP6500AA AF: 0.0248 AC: 109

ESP6500EA AF: 0.0693 AC: 596

ExAC AF: 0.0614 AC: 7416

Asia WGS AF: 0.0790 AC: 272 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 15, 2015	- -

Neuronal ceroid lipofuscinosis 10 Benign:2

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Sep 21, 2016	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Neuronal ceroid lipofuscinosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.017
DANN	Benign	0.87
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N
PROVEAN	Benign	0.0	N
REVEL	Benign	0.13
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.19	T
ClinPred		0.0022	T
GERP RS		-5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs78735768; hg19: chr11-1775385; COSMIC: COSV52589176; COSMIC: COSV52589176;