rs17571

Variant names:

• chr11-1761364-G-A
• rs17571
• NM_001909.5:c.173C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-1761364-G-A
• chr11-1761364-G-T
• chr11-1761364-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001909.5(CTSD):​c.173C>T​(p.Ala58Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.078 in 1,613,604 control chromosomes in the GnomAD database, including 5,321 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A58E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.063 (350 hom., cov: 33)
  • Exomes 𝑓: 0.080 (4971 hom.)
• Consequence: CTSD NM_001909.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.354
• Publications: 72 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]

ENSG00000250644 (HGNC:):

PRADX (HGNC:40168): (PRC2 and DDX5 associated lncRNA)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018743575).
• BP6: Variant 11-1761364-G-A is Benign according to our data. Variant chr11-1761364-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0825 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.173C>T	p.Ala58Val	missense	Exon 2 of 9	NP_001900.1	P07339
	PRADX	NR_182291.1		n.893G>A		non_coding_transcript_exon	Exon 2 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSD	ENST00000236671.7	TSL:1 MANE Select	c.173C>T	p.Ala58Val	missense	Exon 2 of 9	ENSP00000236671.2	P07339
	ENSG00000250644	ENST00000636615.1	TSL:5	c.173C>T	p.Ala58Val	missense	Exon 2 of 10	ENSP00000490014.1	A0A1B0GU92
	PRADX	ENST00000449248.1	TSL:1	n.893G>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.0629 AC: 9564 AN: 152140 Hom.: 347 Cov.: 33

Gnomad AFR AF: 0.0298

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0720

Gnomad ASJ AF: 0.0905

Gnomad EAS AF: 0.0285

Gnomad SAS AF: 0.0898

Gnomad FIN AF: 0.0461

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0826

Gnomad OTH AF: 0.0780

GnomAD2 exomes AF: 0.0699 AC: 17549 AN: 250886 AF XY: 0.0737

Gnomad AFR exome AF: 0.0276

Gnomad AMR exome AF: 0.0462

Gnomad ASJ exome AF: 0.0948

Gnomad EAS exome AF: 0.0327

Gnomad FIN exome AF: 0.0526

Gnomad NFE exome AF: 0.0827

Gnomad OTH exome AF: 0.0868

GnomAD4 exome AF: 0.0796 AC: 116346 AN: 1461346 Hom.: 4971 Cov.: 32 AF XY: 0.0802 AC XY: 58300 AN XY: 726984

African (AFR) AF: 0.0290 AC: 972 AN: 33480

American (AMR) AF: 0.0473 AC: 2114 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0883 AC: 2308 AN: 26134

East Asian (EAS) AF: 0.0245 AC: 974 AN: 39700

South Asian (SAS) AF: 0.0951 AC: 8201 AN: 86258

European-Finnish (FIN) AF: 0.0514 AC: 2723 AN: 53018

Middle Eastern (MID) AF: 0.126 AC: 725 AN: 5768

European-Non Finnish (NFE) AF: 0.0840 AC: 93445 AN: 1111882

Other (OTH) AF: 0.0809 AC: 4884 AN: 60386

GnomAD4 genome AF: 0.0628 AC: 9566 AN: 152258 Hom.: 350 Cov.: 33 AF XY: 0.0612 AC XY: 4557 AN XY: 74450

African (AFR) AF: 0.0298 AC: 1239 AN: 41560

American (AMR) AF: 0.0719 AC: 1100 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0905 AC: 314 AN: 3470

East Asian (EAS) AF: 0.0284 AC: 147 AN: 5174

South Asian (SAS) AF: 0.0894 AC: 432 AN: 4830

European-Finnish (FIN) AF: 0.0461 AC: 489 AN: 10614

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.0827 AC: 5621 AN: 67998

Other (OTH) AF: 0.0791 AC: 167 AN: 2112

Alfa AF: 0.0765 Hom.: 2009

Bravo AF: 0.0618

TwinsUK AF: 0.0777 AC: 288

ALSPAC AF: 0.0791 AC: 305

ESP6500AA AF: 0.0318 AC: 140

ESP6500EA AF: 0.0811 AC: 697

ExAC AF: 0.0702 AC: 8517

Asia WGS AF: 0.0820 AC: 285 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Neuronal ceroid lipofuscinosis 10 (3)
-	-	3	not provided (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	Neuronal ceroid lipofuscinosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	9.7
DANN	Benign	0.82
DEOGEN2	Benign	0.35	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PhyloP100		-0.35
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.11
Sift	Benign	0.66	T
Sift4G	Benign	0.31	T
Polyphen		0.18	B
Vest4		0.058
MPC		0.53
ClinPred		0.0019	T
GERP RS		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.019
gMVP		0.51
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17571; hg19: chr11-1782594; COSMIC: COSV52589252; COSMIC: COSV52589252;