11-1753559-T-G

Variant names:

• chr11-1753559-T-G
• NM_001909.5:c.1183A>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001909.5(CTSD):​c.1183A>C​(p.Thr395Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CTSD NM_001909.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.25

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSD	NM_001909.5	c.1183A>C	p.Thr395Pro	missense_variant	Exon 9 of 9	ENST00000236671.7	NP_001900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSD	ENST00000236671.7	c.1183A>C	p.Thr395Pro	missense_variant	Exon 9 of 9	1	NM_001909.5	ENSP00000236671.2
ENSG00000250644	ENST00000636615.1	c.1071+244A>C		intron_variant	Intron 8 of 9	5		ENSP00000490014.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D;T;.;T;.;T;.
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Pathogenic	4.0	H;.;.;.;.;.;.
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-4.9	D;.;.;.;.;.;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0010	D;.;.;.;.;.;D
Sift4G	Uncertain	0.024	D;.;.;.;.;.;D
Polyphen		1.0	D;.;.;.;.;.;.
Vest4		0.69
MutPred		0.77		Loss of phosphorylation at T395 (P = 0.0284);.;.;.;.;.;.;
MVP		0.80
MPC		1.6
ClinPred		1.0	D
GERP RS		-0.069
Varity_R		0.99
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr11-1774789;