7-117614713-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3BS2_Supporting

The NM_000492.4(CFTR):​c.3468G>T​(p.Leu1156Phe) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000379 in 1,602,446 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L1156L) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00040 ( 7 hom. )

Consequence

CFTR
NM_000492.4 missense, splice_region

Scores

6
7
6
Splicing: ADA: 0.9999
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1

Conservation

PhyloP100: 6.67
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP3
Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, dbscSNV1_ADA, dbscSNV1_RF, max_spliceai, Eigen, M_CAP [when BayesDel_addAF, FATHMM_MKL, MetaRNN, MutationTaster, PROVEAN was below the threshold]
BS2
High Homozygotes in GnomAdExome4 at 7 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CFTRNM_000492.4 linkc.3468G>T p.Leu1156Phe missense_variant, splice_region_variant Exon 21 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.3468G>T p.Leu1156Phe missense_variant, splice_region_variant Exon 21 of 27 1 NM_000492.4 ENSP00000003084.6 P13569-1

Frequencies

GnomAD3 genomes
AF:
0.000178
AC:
27
AN:
151970
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00520
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000132
AC:
33
AN:
250770
Hom.:
0
AF XY:
0.000118
AC XY:
16
AN XY:
135530
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00163
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000492
GnomAD4 exome
AF:
0.000401
AC:
581
AN:
1450358
Hom.:
7
Cov.:
27
AF XY:
0.000403
AC XY:
291
AN XY:
722280
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0145
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.000100
GnomAD4 genome
AF:
0.000178
AC:
27
AN:
152088
Hom.:
0
Cov.:
31
AF XY:
0.000134
AC XY:
10
AN XY:
74352
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00521
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000119
Hom.:
0
Bravo
AF:
0.0000491
ExAC
AF:
0.000198
AC:
24
Asia WGS
AF:
0.00144
AC:
5
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:8Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Cystic fibrosis Uncertain:3Benign:1
Dec 24, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 29, 2018
Natera, Inc.
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 05, 2018
Mendelics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 29, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.3468G>T variant (also known as p.L1156F), located in coding exon 21 of the CFTR gene, results from a G to T substitution at nucleotide position 3468. The amino acid change results in leucine to phenylalanine at codon 1156, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 21, which makes it likely to have some effect on normal mRNA splicing. This variant has been reported in multiple Japanese individuals with idiopathic, familial, hereditary, and alcoholic pancreatitis, including one individual with alcoholic pancreatitis who was homozygous for this alteration (Nakano E, Dig. Dis. Sci. 2015 May; 60(5):1297-307; Kondo S, Am. J. Physiol. Gastrointest. Liver Physiol. 2015 Aug; 309(4):G260-9). This nucleotide position is highly conserved in available vertebrate species, and this amino acid position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition, as a missense substitution, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:3
Oct 17, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The CFTR c.3468G>T; p.Leu1156Phe variant (rs139729994) has been described in several individuals affected with CFTR-related disorders but is also present in healthy controls (see link for SickKids CFTR database, Iso 2019, Kondo 2015, Li 2022, Nakano 2015). It is reported in ClinVar (Variation ID: 455775) and is observed in the East Asian population at an allele frequency of 0.16% (30/18,378 alleles) in the Genome Aggregation Database (v2.1.1). Additionally, another variant at this codon (c.3468G>A; p.Leu1156Leu) has been described in individuals with a pancreatic sufficient form of cystic fibrosis who harbored another pathogenic variant on the opposite chromosome, in a homozygous individual with pancreatitis, and an individual with congenital bilateral absence of vas deferens (see link for SickKids CFTR database, Claustres 2017). The p.Leu1156Phe variant is in the last nucleotide of exon 21 and computational analyses (Alamut Visual Plus v.1.5.1) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. In vitro analyses of this variant demonstrate reduced protein expression and chloride transport activity when found with the Met470Val variant on the same chromosome, but no effect was seen in the presence of this variant alone (Kondo 2015). Due to conflicting information, the clinical significance of this variant is uncertain at this time. References: Link to Cystic Fibrosis Mutation Database: http://www.genet.sickkids.on.ca/ Claustres M et al. CFTR-France, a national relational patient database for sharing genetic and phenotypic data associated with rare CFTR variants. Hum Mutat. 2017 Oct;38(10):1297-1315. PMID: 28603918. Iso M et al. The CFTR gene variants in Japanese children with idiopathic pancreatitis. Hum Genome Var. 2019 Apr 11;6:17. PMID: 30992994. Li Q et al. Mutations in CFTR genes are associated with oligoasthenospermia in infertile men undergoing IVF. Andrologia. 2022 Apr;54(3):e14355. PMID: 34931337. Kondo S et al. Functional characteristics of L1156F-CFTR associated with alcoholic chronic pancreatitis in Japanese. Am J Physiol Gastrointest Liver Physiol. 2015 Aug 15;309(4):G260-9. PMID: 26089335. Nakano E et al. Targeted next-generation sequencing effectively analyzed the cystic fibrosis transmembrane conductance regulator gene in pancreatitis. Dig Dis Sci. 2015 May;60(5):1297-307. PMID: 25492507. -

Oct 04, 2021
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 12, 2023
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PP3, PM2_moderate -

not specified Uncertain:1
Dec 19, 2022
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: CFTR c.3468G>T (p.Leu1156Phe) involves the alteration of a conserved nucleotide located in the last position of exon 21. 3/4 splice prediction tools predict a slight weakening of a canonical 5' splice donor site. However, these predictions have yet to be confirmed by functional studies. In the absence of splice change the variant would result in a non-conservative amino acid change that is located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251130 control chromosomes, predominantly within the East Asian subpopulation at a frequency of 0.0016 in the gnomAD database. This frequency is lower than estimated for a pathogenic variant in CFTR causing CFTR-related diseases (0.0016 vs. 0.013), allowing no conclusion about variant significance. The variant has been reported in two publications to be statistically associated with idiopathic and alcoholic chronic pancreatitis in Japanese patients (example, Kondo 2015, Nakano 2015, Iso_2019), however the sample size in these case-control studies was small and the authors did not adjust for the effect of other likely pathogenic or pathogenic CFTR, SPINK1, and CTRC variants that were found in co-occurrence in several patients in these cohorts. Another study reports this variant as a non-informative genotype (second allele or zygosity not specified) in at-least two Chinese individuals, one with CAVD and another with oligoasthenospermia (example, Li_2022). These report(s) do not provide unequivocal conclusions about association of the variant with CFTR-Related Diseases. At least one publication reports experimental evidence evaluating an impact on protein function, showing that CFTR expression, Cl- current, HCO3- and Cl- transport was not different from wild-type in cells expressing the variant of interest, however, Cl-/HCO3- exchange activity was reduced to 30% of the wild-type levels and two patients had higher than normal sweat chloride levels (Kondo 2015). The variant of interest in combination with a benign polymorphism (V470M) had reduced CFTR expression (to 60-70%), CFTR-mediated HCO3-/Cl- transport (to 50-60%) and the Cl-/HCO3-exchange activity (to 2030%) compared to wild-type (Kondo 2015). Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely benign (n=1), VUS (n=4). Based on all these conflicting evidence outlined above, the variant was classified as a VUS, until more definitive functional and clinical studies become available. -

CFTR-related disorder Uncertain:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.39
BayesDel_addAF
Benign
-0.032
T
BayesDel_noAF
Pathogenic
0.17
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.43
T;.;.;T;.
Eigen
Pathogenic
0.73
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.97
D;D;D;D;D
M_CAP
Pathogenic
0.73
D
MetaRNN
Benign
0.026
T;T;T;T;T
MetaSVM
Benign
-0.79
T
MutationAssessor
Uncertain
2.2
M;.;.;.;.
PrimateAI
Uncertain
0.74
T
PROVEAN
Benign
-0.73
N;.;.;N;.
REVEL
Uncertain
0.60
Sift
Benign
0.16
T;.;.;T;.
Sift4G
Uncertain
0.0020
D;.;.;D;.
Polyphen
0.99
D;.;.;.;.
Vest4
0.73
MutPred
0.38
Loss of stability (P = 0.0994);.;.;.;.;
MVP
1.0
MPC
0.0052
ClinPred
0.29
T
GERP RS
5.9
Varity_R
0.32
gMVP
0.84

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.84
SpliceAI score (max)
0.71
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.71
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: rs139729994; hg19: chr7-117254767; API