NM_004937.3:c.*2569C>T

Variant names:

• chr17-3662938-C-T
• rs7093
• NM_004937.3:c.*2569C>T

Variant summary

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

The NM_004937.3(CTNS):​c.*2569C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.347 in 152,126 control chromosomes in the GnomAD database, including 9,808 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9807 hom., cov: 33)
  • Exomes 𝑓: 0.30 (1 hom.)
• Consequence: CTNS NM_004937.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.10
• Publications: 7 publications found

Genes affected

CTNS (HGNC:2518): (cystinosin, lysosomal cystine transporter) This gene encodes a seven-transmembrane domain protein that functions to transport cystine out of lysosomes. Its activity is driven by the H+ electrochemical gradient of the lysosomal membrane. Mutations in this gene cause cystinosis, a lysosomal storage disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2009]

TAX1BP3 (HGNC:30684): (Tax1 binding protein 3) This gene encodes a small, highly conserved protein with a single PDZ domain. PDZ (PSD-95/Discs large/ZO-1 homologous) domains promote protein-protein interactions that affect cell signaling, adhesion, protein scaffolding, and receptor and ion transporter functions. The encoded protein interacts with a large number of target proteins that play roles in signaling pathways; for example, it interacts with Rho A and glutaminase L and also acts as a negative regulator of the Wnt/beta-catenin signaling pathway. This protein was first identified as binding to the T-cell leukaemia virus (HTLV1) Tax oncoprotein. Overexpression of this gene has been implicated in altered cancer cell adhesion, migration and metastasis. The encoded protein also modulates the localization and density of inwardly rectifying potassium channel 2.3 (Kir2.3). To date, this protein has been shown to play a role in cell proliferation, development, stress response, and polarization. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Apr 2017]

P2RX5-TAX1BP3 (HGNC:49191): (P2RX5-TAX1BP3 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring P2RX5 (purinergic receptor P2X, ligand-gated ion channel, 5) and TAX1BP3 (Tax1 binding protein 3) genes on chromosome 17. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Mar 2011]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 17-3662938-C-T is Benign according to our data. Variant chr17-3662938-C-T is described in ClinVar as Benign. ClinVar VariationId is 322920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.487 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004937.3. 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
	CTNS	NM_004937.3	MANE Select	c.*2569C>T		3_prime_UTR	Exon 12 of 12	NP_004928.2	O60931-1
	TAX1BP3	NM_014604.4	MANE Select	c.*810G>A		3_prime_UTR	Exon 4 of 4	NP_055419.1	O14907
	CTNS	NM_001031681.3		c.*2204C>T		3_prime_UTR	Exon 13 of 13	NP_001026851.2	O60931-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNS	ENST00000046640.9	TSL:1 MANE Select	c.*2569C>T		3_prime_UTR	Exon 12 of 12	ENSP00000046640.4	O60931-1
	TAX1BP3	ENST00000225525.4	TSL:1 MANE Select	c.*810G>A		3_prime_UTR	Exon 4 of 4	ENSP00000225525.3	O14907
	TAX1BP3	ENST00000874102.1		c.*810G>A		3_prime_UTR	Exon 4 of 4	ENSP00000544161.1

Frequencies

GnomAD3 genomes AF: 0.347 AC: 52714 AN: 151998 Hom.: 9805 Cov.: 33

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.419

Gnomad AMR AF: 0.395

Gnomad ASJ AF: 0.467

Gnomad EAS AF: 0.503

Gnomad SAS AF: 0.441

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.400

Gnomad OTH AF: 0.357

GnomAD4 exome AF: 0.300 AC: 3 AN: 10 Hom.: 1 Cov.: 0 AF XY: 0.167 AC XY: 1 AN XY: 6

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.250 AC: 1 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 2 AN: 4

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.347 AC: 52738 AN: 152116 Hom.: 9807 Cov.: 33 AF XY: 0.345 AC XY: 25674 AN XY: 74342

African (AFR) AF: 0.214 AC: 8900 AN: 41498

American (AMR) AF: 0.396 AC: 6047 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.467 AC: 1621 AN: 3472

East Asian (EAS) AF: 0.503 AC: 2596 AN: 5164

South Asian (SAS) AF: 0.440 AC: 2125 AN: 4830

European-Finnish (FIN) AF: 0.285 AC: 3013 AN: 10586

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.400 AC: 27176 AN: 67968

Other (OTH) AF: 0.356 AC: 752 AN: 2114

Alfa AF: 0.379 Hom.: 5131

Bravo AF: 0.348

Asia WGS AF: 0.435 AC: 1513 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Nephropathic cystinosis (1)
-	-	1	not provided (1)
-	-	1	Ocular cystinosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.58
DANN	Benign	0.63
PhyloP100		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.97
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: rs7093; hg19: chr17-3566232;