chr17-3647455-A-T

Position:

• chr17-3647455-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_001374493.1(CTNS):​c.-284A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,772 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CTNS NM_001374493.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: -0.372

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]

CTNS (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-3647455-A-T is Pathogenic according to our data. Variant chr17-3647455-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 555150.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.22018778). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTNS	NM_004937.3	c.73A>T	p.Ser25Cys	missense_variant	4/12	ENST00000046640.9	NP_004928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTNS	ENST00000046640.9	c.73A>T	p.Ser25Cys	missense_variant	4/12	1	NM_004937.3	ENSP00000046640.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461772 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727196

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nephropathic cystinosis Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 19, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 02, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	9.2
DANN	Uncertain	0.98
DEOGEN2	Benign	0.34	T;.;.;.;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.57	T;T;T;T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.22	T;T;T;T;T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	1.7	L;L;.;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.1	N;N;D;D;.
REVEL	Uncertain	0.35
Sift	Uncertain	0.028	D;D;T;T;.
Sift4G	Uncertain	0.060	T;T;T;T;T
Polyphen		0.84	P;D;.;.;.
Vest4		0.30
MutPred		0.31		Loss of disorder (P = 0.0268);Loss of disorder (P = 0.0268);Loss of disorder (P = 0.0268);Loss of disorder (P = 0.0268);Loss of disorder (P = 0.0268);
MVP		0.81
MPC		0.44
ClinPred		0.40	T
GERP RS		-6.3
Varity_R		0.055
gMVP		0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs777367316; hg19: chr17-3550749;