chr11-1761326-G-A

Position:

• chr11-1761326-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001909.5(CTSD):​c.211C>T​(p.Leu71Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CTSD NM_001909.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.07

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]

ENSG00000250644 (HGNC:):

PRADX (HGNC:40168): (PRC2 and DDX5 associated lncRNA)

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.785

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTSD	NM_001909.5	c.211C>T	p.Leu71Phe	missense_variant	2/9	ENST00000236671.7	NP_001900.1
PRADX	NR_182291.1	n.855G>A		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSD	ENST00000236671.7	c.211C>T	p.Leu71Phe	missense_variant	2/9	1	NM_001909.5	ENSP00000236671.2
ENSG00000250644	ENST00000636615.1	c.211C>T	p.Leu71Phe	missense_variant	2/10	5		ENSP00000490014.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neuronal ceroid lipofuscinosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 01, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CTSD protein function. This variant has not been reported in the literature in individuals affected with CTSD-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 71 of the CTSD protein (p.Leu71Phe). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	.;.;D;T;.;.;T;.;.;T
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Pathogenic	3.2	.;.;M;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.8	.;.;D;.;.;.;.;D;D;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.0010	.;.;D;.;.;.;.;D;D;.
Sift4G	Uncertain	0.0020	.;.;D;.;.;.;.;D;.;.
Polyphen		1.0	.;.;D;.;.;.;.;.;.;.
Vest4		0.70
MutPred		0.61		Gain of methylation at K72 (P = 0.066);Gain of methylation at K72 (P = 0.066);Gain of methylation at K72 (P = 0.066);Gain of methylation at K72 (P = 0.066);Gain of methylation at K72 (P = 0.066);Gain of methylation at K72 (P = 0.066);Gain of methylation at K72 (P = 0.066);.;.;.;
MVP		0.65
MPC		1.5
ClinPred		0.99	D
GERP RS		2.8
Varity_R		0.82
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-1782556;