chr11-1753203-C-T

Variant names:

• chr11-1753203-C-T
• rs113940256
• NM_001909.5:c.*300G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001909.5(CTSD):​c.*300G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00572 in 462,604 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (49 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (12 hom.)
• Consequence: CTSD NM_001909.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.282
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 11-1753203-C-T is Benign according to our data. Variant chr11-1753203-C-T is described in ClinVar as Benign. ClinVar VariationId is 303828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.014 (2131/152282) while in subpopulation AFR AF = 0.0486 (2020/41562). AF 95% confidence interval is 0.0468. There are 49 homozygotes in GnomAd4. There are 1026 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 49 AR gene

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.*300G>A		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.*300G>A		3_prime_UTR	Exon 9 of 9	ENSP00000236671.2	P07339
	ENSG00000250644	ENST00000636615.1	TSL:5	c.1071+600G>A		intron	N/A	ENSP00000490014.1	A0A1B0GU92
	CTSD	ENST00000962446.1		c.*300G>A		3_prime_UTR	Exon 10 of 10	ENSP00000632505.1

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2128 AN: 152164 Hom.: 49 Cov.: 33

Gnomad AFR AF: 0.0487

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00814

GnomAD4 exome AF: 0.00167 AC: 517 AN: 310322 Hom.: 12 Cov.: 0 AF XY: 0.00138 AC XY: 228 AN XY: 165250

African (AFR) AF: 0.0449 AC: 407 AN: 9060

American (AMR) AF: 0.00261 AC: 37 AN: 14158

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9080

East Asian (EAS) AF: 0.0000551 AC: 1 AN: 18162

South Asian (SAS) AF: 0.000412 AC: 18 AN: 43644

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16060

Middle Eastern (MID) AF: 0.000776 AC: 1 AN: 1288

European-Non Finnish (NFE) AF: 0.0000330 AC: 6 AN: 181578

Other (OTH) AF: 0.00272 AC: 47 AN: 17292

GnomAD4 genome AF: 0.0140 AC: 2131 AN: 152282 Hom.: 49 Cov.: 33 AF XY: 0.0138 AC XY: 1026 AN XY: 74448

African (AFR) AF: 0.0486 AC: 2020 AN: 41562

American (AMR) AF: 0.00529 AC: 81 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68004

Other (OTH) AF: 0.00806 AC: 17 AN: 2110

Alfa AF: 0.00391 Hom.: 5

Bravo AF: 0.0160

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Neuronal ceroid lipofuscinosis 10 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.1
DANN	Benign	0.57
PhyloP100		0.28
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: rs113940256; hg19: chr11-1774433;