chr11-1758975-A-G

Variant names:

• chr11-1758975-A-G
• rs11555039
• NM_001909.5:c.465T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001909.5(CTSD):​c.465T>C​(p.Thr155Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.083 in 1,606,950 control chromosomes in the GnomAD database, including 5,929 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (560 hom., cov: 33)
  • Exomes 𝑓: 0.083 (5369 hom.)
• Consequence: CTSD NM_001909.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -4.36
• Publications: 15 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.052).
• BP6: Variant 11-1758975-A-G is Benign according to our data. Variant chr11-1758975-A-G is described in ClinVar as Benign. ClinVar VariationId is 128876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.36 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0943 is higher than 0.05.

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.465T>C	p.Thr155Thr	synonymous	Exon 4 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.465T>C	p.Thr155Thr	synonymous	Exon 4 of 9	ENSP00000236671.2	P07339
	ENSG00000250644	ENST00000636615.1	TSL:5	c.465T>C	p.Thr155Thr	synonymous	Exon 4 of 10	ENSP00000490014.1	A0A1B0GU92
	ENSG00000250644	ENST00000636397.1	TSL:5	c.465T>C	p.Thr155Thr	synonymous	Exon 4 of 10	ENSP00000489910.1	A0A1B0GU03

Frequencies

GnomAD3 genomes AF: 0.0836 AC: 12719 AN: 152086 Hom.: 553 Cov.: 33

Gnomad AFR AF: 0.0967

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0812

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.0289

Gnomad SAS AF: 0.0924

Gnomad FIN AF: 0.0459

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.0848

Gnomad OTH AF: 0.0917

GnomAD2 exomes AF: 0.0770 AC: 19317 AN: 250942 AF XY: 0.0793

Gnomad AFR exome AF: 0.0984

Gnomad AMR exome AF: 0.0504

Gnomad ASJ exome AF: 0.109

Gnomad EAS exome AF: 0.0328

Gnomad FIN exome AF: 0.0526

Gnomad NFE exome AF: 0.0848

Gnomad OTH exome AF: 0.0929

GnomAD4 exome AF: 0.0830 AC: 120716 AN: 1454746 Hom.: 5369 Cov.: 30 AF XY: 0.0834 AC XY: 60429 AN XY: 724258

African (AFR) AF: 0.102 AC: 3391 AN: 33308

American (AMR) AF: 0.0521 AC: 2329 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 2715 AN: 26074

East Asian (EAS) AF: 0.0245 AC: 971 AN: 39666

South Asian (SAS) AF: 0.0976 AC: 8408 AN: 86108

European-Finnish (FIN) AF: 0.0514 AC: 2740 AN: 53344

Middle Eastern (MID) AF: 0.140 AC: 805 AN: 5756

European-Non Finnish (NFE) AF: 0.0851 AC: 94075 AN: 1105640

Other (OTH) AF: 0.0878 AC: 5282 AN: 60146

GnomAD4 genome AF: 0.0837 AC: 12736 AN: 152204 Hom.: 560 Cov.: 33 AF XY: 0.0809 AC XY: 6022 AN XY: 74420

African (AFR) AF: 0.0968 AC: 4020 AN: 41528

American (AMR) AF: 0.0811 AC: 1241 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 374 AN: 3472

East Asian (EAS) AF: 0.0288 AC: 149 AN: 5170

South Asian (SAS) AF: 0.0921 AC: 444 AN: 4822

European-Finnish (FIN) AF: 0.0459 AC: 487 AN: 10604

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.0848 AC: 5765 AN: 67996

Other (OTH) AF: 0.0935 AC: 197 AN: 2106

Alfa AF: 0.0864 Hom.: 363

Bravo AF: 0.0856

Asia WGS AF: 0.0910 AC: 314 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Neuronal ceroid lipofuscinosis 10 (3)
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	Neuronal ceroid lipofuscinosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.30
DANN	Benign	0.65
PhyloP100		-4.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs11555039; hg19: chr11-1780205; COSMIC: COSV108036006; COSMIC: COSV108036006;