7-117590439-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_000492.4(CFTR):​c.1766G>T​(p.Ser589Ile) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

CFTR
NM_000492.4 missense, splice_region

Scores

4
10
5
Splicing: ADA: 0.9999
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2O:1

Conservation

PhyloP100: 5.68
Variant links:
Genes affected
CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1
In a domain ABC transporter 1 (size 223) in uniprot entity CFTR_HUMAN there are 54 pathogenic changes around while only 9 benign (86%) in NM_000492.4
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 7-117590439-G-T is Pathogenic according to our data. Variant chr7-117590439-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CFTRNM_000492.4 linkc.1766G>T p.Ser589Ile missense_variant, splice_region_variant Exon 13 of 27 ENST00000003084.11 NP_000483.3 P13569-1A0A024R730

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CFTRENST00000003084.11 linkc.1766G>T p.Ser589Ile missense_variant, splice_region_variant Exon 13 of 27 1 NM_000492.4 ENSP00000003084.6 P13569-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Cystic fibrosis Pathogenic:1Other:1
Jun 25, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 589 of the CFTR protein (p.Ser589Ile). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 16423550, 22362925, 26500004; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 53384). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 12, but is expected to preserve the integrity of the reading-frame (PMID: 22362925). This variant disrupts the c.1766G nucleotide in the CFTR gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 16379540; Invitae). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. -

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ClinVar Staff, National Center for Biotechnology Information (NCBI)
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1
-
Baylor Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.22
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.74
D;.;T;.
Eigen
Benign
0.037
Eigen_PC
Benign
0.21
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.96
D;D;D;D
M_CAP
Pathogenic
0.35
D
MetaRNN
Uncertain
0.74
D;D;D;D
MetaSVM
Uncertain
0.11
D
MutationAssessor
Benign
0.13
N;.;.;.
PrimateAI
Uncertain
0.50
T
PROVEAN
Uncertain
-3.3
D;.;D;.
REVEL
Pathogenic
0.72
Sift
Uncertain
0.021
D;.;D;.
Sift4G
Uncertain
0.020
D;.;D;.
Polyphen
0.29
B;.;.;.
Vest4
0.77
MutPred
0.72
Gain of catalytic residue at L594 (P = 0.0857);.;.;.;
MVP
1.0
MPC
0.0039
ClinPred
0.92
D
GERP RS
4.8
Varity_R
0.82
gMVP
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
1.0
SpliceAI score (max)
0.85
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.85
Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs397508300; hg19: chr7-117230493; API