rs751538234

Variant names:

• chr11-1752809-C-T
• rs751538234
• NM_001909.5:c.*694G>A

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.*694G>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 0.00112 in 155,588 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 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00062 (0 hom.)
• Consequence: CTSD NM_001909.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -6.61
• 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp

ENSG00000250644 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00114 (173/152374) while in subpopulation AMR AF = 0.0032 (49/15312). AF 95% confidence interval is 0.00249. There are 0 homozygotes in GnomAd4. There are 80 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.*694G>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.*694G>A		3_prime_UTR	Exon 9 of 9	ENSP00000236671.2	P07339
	ENSG00000250644	ENST00000636615.1	TSL:5	c.1071+994G>A		intron	N/A	ENSP00000490014.1	A0A1B0GU92
	CTSD	ENST00000962446.1		c.*694G>A		3_prime_UTR	Exon 10 of 10	ENSP00000632505.1

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 173 AN: 152256 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00320

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.000622 AC: 2 AN: 3214 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 1684

African (AFR) AF: 0.00 AC: 0 AN: 18

American (AMR) AF: 0.00281 AC: 1 AN: 356

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22

East Asian (EAS) AF: 0.00 AC: 0 AN: 32

South Asian (SAS) AF: 0.00 AC: 0 AN: 300

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 56

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 40

European-Non Finnish (NFE) AF: 0.000442 AC: 1 AN: 2262

Other (OTH) AF: 0.00 AC: 0 AN: 128

GnomAD4 genome AF: 0.00114 AC: 173 AN: 152374 Hom.: 0 Cov.: 33 AF XY: 0.00107 AC XY: 80 AN XY: 74512

African (AFR) AF: 0.000409 AC: 17 AN: 41596

American (AMR) AF: 0.00320 AC: 49 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00121 AC: 82 AN: 68032

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00166 Hom.: 0

Bravo AF: 0.00139

ClinVar

ClinVar submissions as Germline

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	-0.90
CADD	Benign	0.22
DANN	Benign	0.59
PhyloP100		-6.6
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.3

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: rs751538234; hg19: chr11-1774039;