chr17-3656579-A-T

Position:

• chr17-3656579-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_004937.3(CTNS):​c.554A>T​(p.Tyr185Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 28)
• Consequence: CTNS NM_004937.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.282

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.

• PM1: In a domain PQ-loop 1 (size 66) in uniprot entity CTNS_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_004937.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0935649).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTNS	NM_004937.3	c.554A>T	p.Tyr185Phe	missense_variant	8/12	ENST00000046640.9	NP_004928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTNS	ENST00000046640.9	c.554A>T	p.Tyr185Phe	missense_variant	8/12	1	NM_004937.3	ENSP00000046640.4

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Cystinosis Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 21, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	0.0044	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	7.1
DANN	Benign	0.84
DEOGEN2	Benign	0.35	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.83	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.094	T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	0.81	L;L
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.21
Sift	Benign	0.69	T;T
Sift4G	Benign	0.70	T;T
Polyphen		0.0020	B;B
Vest4		0.22
MutPred		0.27		Loss of sheet (P = 0.007);Loss of sheet (P = 0.007);
MVP		0.76
MPC		0.15
ClinPred		0.022	T
GERP RS		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.063
gMVP		0.63

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

Publications

LitVar

Other links and lift over

dbSNP: rs886038378; hg19: chr17-3559873;