rs397508751

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4_StrongBS2_Supporting

The NM_000492.4(CFTR):c.547C>A(p.Leu183Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,602,238 control chromosomes in the GnomAD database, including 2 homozygotes. 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: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 2 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.52

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]

CFTR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1

In a domain ABC transmembrane type-1 1 (size 284) in uniprot entity CFTR_HUMAN there are 65 pathogenic changes around while only 10 benign (87%) in NM_000492.4

BP4

Computational evidence support a benign effect (MetaRNN=0.02408579).

BS2

High Homozygotes in GnomAdExome4 at 2 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/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.547C>A	p.Leu183Ile	missense_variant	5/27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.547C>A	p.Leu183Ile	missense_variant	5/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152156

Hom.:

Cov.:

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:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000299

AC:

AN:

250676

Hom.:

AF XY:

0.000369

AC XY:

AN XY:

135546

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00242

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000177

AC:

256

AN:

1449966

Hom.:

Cov.:

AF XY:

0.000260

AC XY:

188

AN XY:

722146

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00276

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000317

GnomAD4 genome

AF:

0.000105

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00331

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.000371

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:3Benign:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 22, 2023	The p.L183I variant (also known as c.547C>A), located in coding exon 5 of the CFTR gene, results from a C to A substitution at nucleotide position 547. The leucine at codon 183 is replaced by isoleucine, an amino acid with highly similar properties. This variant was identified in an individual with lower respiratory tract infections, sinusitis, failure to thrive and elevated sweat chloride levels of 57 and 60; a second CFTR alteration was not identified (Shastri SS et al. J. Cyst. Fibros., 2008 Mar;7:110-5). It was also identified in a 28-year-old male with normal sweat chloride levels, bronchiectasis, and pulmonary non-tuberculosis mycobacterial infection; a second CFTR alteration was not identified (Ziedalski TM et al. Chest, 2006 Oct;130:995-1002). An in vitro study attempting to identify exonic alterations which weaken core splicing motifs using hybrid minigene constructs revealed a increased basal exon skipping of exon 5 with this particular nucleotide substitution compared to the wild type construct (Aissat A et al. Hum. Mutat., 2013 Jun;34:873-81). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Mar 01, 2023	The missense variant c.547C>A(p.Leu183Ile) in the CFTR gene has been reported previously in a heterozygous state in individuals affected with asthma and chronic pancreatitis. An in vitro study attempting to identify exonic alterations which weaken core splicing motifs using hybrid minigene constructs revealed an increased basal exon skipping of exon 5 with this particular nucleotide substitution compared to the wild-type construct (Muthuswamy et al., 2014; Aissat et al., 2013). This variant is reported with the allele frequency (0.02%) in the gnomAD Exomes and novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance/ Likely Benign. The amino acid Leucine at position 183 is changed to a Isoleucine changing protein sequence and it might alter its composition and physico- chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Leu183Ile in CFTR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Based on available evidence to date, the clinical significance of this alteration remains unclear. For these reasons, this variant has been classified as Uncertain Significance. -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	- -

not provided

Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 30, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 11, 2020

Variant summary: CFTR c.547C>A (p.Leu183Ile) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 250676 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (0.0003 vs 0.013), allowing no conclusion about variant significance. c.547C>A has been reported in the literature in individuals affected with Cystic Fibrosis or CFTR related disorders (Ziedalski_2006, Shastri_2008). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported, although one study showed this variant did not lead to exon skipping (Aissat_2013). One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

CFTR-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 10, 2024

The CFTR c.547C>A variant is predicted to result in the amino acid substitution p.Leu183Ile. This variant has been reported in a single patient with cystic fibrosis (in the absence of a second pathogenic variant) and another patient with CF-related symptoms (with normal sweat chloride levels) (Ziedalski et al 2006. PubMed ID: 17035430 and Shastri et al. 2008. PubMed ID: 17716958, respectively). In a hybrid minigene assay, the c.547C>A variant increased exon skipping by ~10% compared to wild-type cells in vitro (Aissat et al 2013. PubMed ID: 23420618). However, it is not clear whether this is sufficient to cause disease. This variant is reported in 0.24% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.064

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.69

D;.;.;.

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Pathogenic

0.75

MetaRNN

Benign

0.024

T;T;T;T

MetaSVM

Pathogenic

0.85

MutationAssessor

Uncertain

2.6

M;.;.;M

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.3

N;.;.;.

REVEL

Uncertain

0.63

Sift

Uncertain

0.019

D;.;.;.

Sift4G

Pathogenic

0.0

D;.;.;.

Polyphen

1.0

D;.;.;.

Vest4

0.68

MutPred

0.63

Gain of catalytic residue at L188 (P = 0.0985);Gain of catalytic residue at L188 (P = 0.0985);Gain of catalytic residue at L188 (P = 0.0985);Gain of catalytic residue at L188 (P = 0.0985);

MVP

1.0

MPC

0.015

ClinPred

0.12

GERP RS

5.5

Varity_R

0.75

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over