NM_001909.5:c.*130G>A

Variant names:

• chr11-1753373-C-T
• rs1002940636
• NM_001909.5:c.*130G>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.*130G>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 0.0000995 in 1,166,310 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: CTSD NM_001909.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.23
• 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=-0.88).
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000104 (105/1014116) while in subpopulation AMR AF = 0.000168 (7/41566). AF 95% confidence interval is 0.000105. There are 1 homozygotes in GnomAdExome4. There are 46 alleles in the male GnomAdExome4 subpopulation. Median coverage is 13. 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.*130G>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.*130G>A		3_prime_UTR	Exon 9 of 9	ENSP00000236671.2	P07339
	ENSG00000250644	ENST00000636615.1	TSL:5	c.1071+430G>A		intron	N/A	ENSP00000490014.1	A0A1B0GU92
	CTSD	ENST00000962446.1		c.*130G>A		3_prime_UTR	Exon 10 of 10	ENSP00000632505.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000104 AC: 105 AN: 1014116 Hom.: 1 Cov.: 13 AF XY: 0.0000884 AC XY: 46 AN XY: 520504

African (AFR) AF: 0.0000406 AC: 1 AN: 24614

American (AMR) AF: 0.000168 AC: 7 AN: 41566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22896

East Asian (EAS) AF: 0.0000269 AC: 1 AN: 37154

South Asian (SAS) AF: 0.00 AC: 0 AN: 76144

European-Finnish (FIN) AF: 0.0000451 AC: 2 AN: 44372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4348

European-Non Finnish (NFE) AF: 0.000127 AC: 91 AN: 717372

Other (OTH) AF: 0.0000657 AC: 3 AN: 45650

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152194 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74336

African (AFR) AF: 0.0000241 AC: 1 AN: 41452

American (AMR) AF: 0.000131 AC: 2 AN: 15284

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000793

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	-0.88
CADD	Benign	1.7
DANN	Benign	0.50
PhyloP100		-1.2
PromoterAI		-0.015	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
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: rs1002940636; hg19: chr11-1774603;