rs74551128

chr7-117548795-C-Achr7-117548795-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000492.4(CFTR):c.1364C>A(p.Ala455Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000631 in 1,600,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A455V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000080 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000061 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Pathogenic practice guideline P:20 O:2
• Conservation: PhyloP100: 7.18

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-AS1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117548795-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 411125.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=6, Likely_pathogenic=2}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935
• PP5: Variant 7-117548795-C-A is Pathogenic according to our data. Variant chr7-117548795-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 7111.Status of the report is practice_guideline, 4 stars. Variant chr7-117548795-C-A is described in Lovd as [Pathogenic]. Variant chr7-117548795-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.1364C>A	p.Ala455Glu	missense_variant	10/27	ENST00000003084.11
CFTR-AS1	NR_149084.1	n.222-6256G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.1364C>A	p.Ala455Glu	missense_variant	10/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.0000799 AC: 12 AN: 150274 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000290

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000163

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000533 AC: 13 AN: 243858 Hom.: 0 AF XY: 0.0000606 AC XY: 8 AN XY: 132024

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000110

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000614 AC: 89 AN: 1450524 Hom.: 0 Cov.: 35 AF XY: 0.0000693 AC XY: 50 AN XY: 721354

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000193

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000725

Gnomad4 OTH exome AF: 0.0000668

GnomAD4 genome AF: 0.0000799 AC: 12 AN: 150274 Hom.: 0 Cov.: 33 AF XY: 0.0000956 AC XY: 7 AN XY: 73246

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000290

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000163

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000855 Hom.: 0

Bravo AF: 0.0000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20 Other:2

Revision: practice guideline

Submissions by phenotype

Cystic fibrosis Pathogenic:10 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1990	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 12, 2019	NM_000492.3(CFTR):c.1364C>A(A455E) is classified as pathogenic in the context of cystic fibrosis and is associated with the non-classic form of disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.1364C>A(A455E) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 455 of the CFTR protein (p.Ala455Glu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with cystic fibrosis (PMID: 2236053, 15371902, 23466340, 23974870). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7111). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 7542778, 23974870). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jul 24, 2020	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 16, 2017	Variant summary: The CFTR c.1364C>A (p.Ala455Glu) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. These predictions were confirmed by functional studies showing the variant to result in <10% chloride conductance (Sosnay_2013). This variant was found in 4/94982 control chromosomes at a frequency of 0.0000421, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant has been reported in numerous affected individuals in the literature and is a known common disease causing mutation. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 07, 2021	The p.A455E pathogenic mutation (also known as c.1364C>A), located in coding exon 10 of the CFTR gene, results from a C to A substitution at nucleotide position 1364. The alanine at codon 455 is replaced by glutamic acid, an amino acid with dissimilar properties. This mutation accounts for approximately 0.3% of cystic fibrosis (CF) alleles (Corvol H et al. Transl Res, 2016 Feb;168:40-9; Brennan ML et al. J Mol Diagn, 2016 Jan;18:3-14) and is typically associated with milder manifestations of CF (Bombieri C et al. Semin Respir Crit Care Med, 2015 Apr;36:180-93). Functional in vitro studies found that cells with this pathogenic mutation maintain 6.8% chloride conduction compared to wild-type (Sosnay PR et al. Nat Genet. 2013;45(10):1160-1167). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, practice guideline	curation	American College of Medical Genetics and Genomics (ACMG)	Mar 03, 2004	- -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 22, 2022	Published functional studies demonstrate a damaging effect: reduced levels of mature CFTR protein and chloride transport compared to wildtype (Sheppard et al, 1995; VanGoor et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21520337, 23420618, 7534226, 9402971, 32429104, 22975760, 25489051, 22658665, 23891399, 24440181, 23378603, 23974870, 20021716, 2236053, 18456578, 29261177, 10777368, 24416359, 7542778, 32204475, 31036917, 8886242, 22390181, 32848127) -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

CFTR-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 17, 2017

- -

Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 21, 2023

- -

ivacaftor response - Efficacy Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Efficacy

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.47
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0030	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.95
MVP		1.0
MPC		0.0073
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.98
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs74551128; hg19: chr7-117188849;