chr11-1753145-G-A

Variant names:

• chr11-1753145-G-A
• rs542969755
• NM_001909.5:c.*358C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_001909.5(CTSD):​c.*358C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000243 in 362,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: CTSD NM_001909.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.89
• Publications: 0 publications found

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]

CTSD Gene-Disease associations (from GenCC):

• neuronal ceroid lipofuscinosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• neuronal ceroid lipofuscinosis 10

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P

ENSG00000250644 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000295 (45/152306) while in subpopulation AMR AF = 0.000392 (6/15302). AF 95% confidence interval is 0.000222. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001909.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSD	NM_001909.5	MANE Select	c.*358C>T		3_prime_UTR	Exon 9 of 9	NP_001900.1	P07339

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSD	ENST00000236671.7	TSL:1 MANE Select	c.*358C>T		3_prime_UTR	Exon 9 of 9	ENSP00000236671.2	P07339
	ENSG00000250644	ENST00000636615.1	TSL:5	c.1071+658C>T		intron	N/A	ENSP00000490014.1	A0A1B0GU92
	CTSD	ENST00000962446.1		c.*358C>T		3_prime_UTR	Exon 10 of 10	ENSP00000632505.1

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.000955

GnomAD4 exome AF: 0.000204 AC: 43 AN: 210440 Hom.: 0 Cov.: 0 AF XY: 0.000193 AC XY: 22 AN XY: 113898

African (AFR) AF: 0.000505 AC: 3 AN: 5944

American (AMR) AF: 0.000202 AC: 2 AN: 9914

Ashkenazi Jewish (ASJ) AF: 0.000747 AC: 4 AN: 5358

East Asian (EAS) AF: 0.00 AC: 0 AN: 8992

South Asian (SAS) AF: 0.0000755 AC: 3 AN: 39734

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9508

Middle Eastern (MID) AF: 0.00130 AC: 1 AN: 768

European-Non Finnish (NFE) AF: 0.000201 AC: 24 AN: 119658

Other (OTH) AF: 0.000568 AC: 6 AN: 10564

GnomAD4 genome AF: 0.000295 AC: 45 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.000295 AC XY: 22 AN XY: 74470

African (AFR) AF: 0.000361 AC: 15 AN: 41572

American (AMR) AF: 0.000392 AC: 6 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68020

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000389

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Neuronal ceroid lipofuscinosis 10 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	2.3
DANN	Benign	0.63
PhyloP100		-3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs542969755; hg19: chr11-1774375;