NM_001909.5:c.1183A>T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001909.5(CTSD):​c.1183A>T​(p.Thr395Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,800 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSD	NM_001909.5	c.1183A>T	p.Thr395Ser	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>T	p.Thr395Ser	missense_variant	Exon 9 of 9	1	NM_001909.5	ENSP00000236671.2
ENSG00000250644	ENST00000636615.1	c.1071+244A>T		intron_variant	Intron 8 of 9	5		ENSP00000490014.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460800 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726738

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Uncertain	0.67	D;T;.;T;.;T;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.73	T;T;T;T;T;T;T
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.54	D;D;D;D;D;D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.6	L;.;.;.;.;.;.
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.4	D;.;.;.;.;.;D
REVEL	Benign	0.23
Sift	Benign	0.062	T;.;.;.;.;.;T
Sift4G	Benign	0.17	T;.;.;.;.;.;T
Polyphen		0.65	P;.;.;.;.;.;.
Vest4		0.43
MutPred		0.71		Loss of phosphorylation at T395 (P = 0.0506);.;.;.;.;.;.;
MVP		0.70
MPC		0.72
ClinPred		0.86	D
GERP RS		-0.069
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.54
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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;