rs397508751

chr7-117534333-C-Achr7-117534333-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1 BP4_Strong

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L183H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (2 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1 O:1
• Conservation: PhyloP100: 3.52

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000492.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.02408579).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.547C>A	p.Leu183Ile	missense_variant	5/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.547C>A	p.Leu183Ile	missense_variant	5/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152156 Hom.: 0 Cov.: 32

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: 75 AN: 250676 Hom.: 0 AF XY: 0.000369 AC XY: 50 AN XY: 135546

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.: 2 Cov.: 26 AF XY: 0.000260 AC XY: 188 AN XY: 722146

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: 16 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74458

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: 45

Asia WGS AF: 0.00144 AC: 6 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Uncertain:3 Benign:1 Other: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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 04, 2024	- -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Uncertain	0.13
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D;.;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Benign	0.024	T;T;T;T
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.6	M;.;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.85	D
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	T
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

Other links and lift over

dbSNP: rs397508751; hg19: chr7-117174387;