rs1800072

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000492.4(CFTR):c.31G>A(p.Val11Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000184 in 1,613,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:13

Conservation

PhyloP100: 1.06

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 Uncertain_significance. Variant got 2 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 76) in uniprot entity CFTR_HUMAN there are 14 pathogenic changes around while only 2 benign (88%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09387541).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.31G>A	p.Val11Ile	missense_variant	1/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.31G>A	p.Val11Ile	missense_variant	1/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000155

AC:

AN:

250988

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135676

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000318

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000184

AC:

269

AN:

1461674

Hom.:

Cov.:

AF XY:

0.000182

AC XY:

132

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000220

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000184

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000329

Hom.:

Bravo

AF:

0.000238

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 17, 2023	The p.V11I variant (also known as c.31G>A), located in coding exon 1 of the CFTR gene, results from a G to A substitution at nucleotide position 31. The valine at codon 11 is replaced by isoleucine, an amino acid with highly similar properties. This variant was detected in an individual with asthma in conjunction with a second CFTR alteration; however, the phase was not provided (Tzetis M et al. Hum. Genet., 2001 Mar;108:216-21). This variant was also identified in an individual with chronic pancreatitis (Palermo JJ et al. Pancreas, 2016 Oct;45:1347-52). In an asymptomatic individual, this variant was detected in conjunction with p.F508del; however, it is unclear if the phase was determined (Claustres M et al. Hum. Mutat., 2017 10;38:1297-1315). This amino acid position is well 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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 11 of the CFTR protein (p.Val11Ile). This variant is present in population databases (rs1800072, gnomAD 0.03%). This missense change has been observed in individual(s) with chronic pancreatitis and clinical manifestations consistent with the spectrum of cystic fibrosis (PMID: 15858154, 27171515). ClinVar contains an entry for this variant (Variation ID: 495928). 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 not expected to disrupt CFTR protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 20, 2017	- -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 17, 2020	In the published literature, this variant has been reported in individuals with CF (PMID: 15858154 (2005)), CFTR-related disorders (PMIDs: 28801929 (2017), 27171515 (2016)), primary sclerosing cholangitis (PMID: 29807875 (2018)), and asthma (PMIDs: 22664493 (2012), 22324837 (2012), 11354633 (2001)). In addition, this variant has been observed in an asymptomatic individual who also carried the CFTR p.Phe508del pathogenic variant (PMID: 28603918 (2017)). The frequency of this variant in the general population, 0.00031 (40/128740 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 07, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 11354633, 27171515, 34996830, 15858154) -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 27, 2018	The CFTR c.31G>A; p.Val11Ile variant (rs1800072), is reported in the literature in individuals affected with chronic pancreatitis or asthma (Maurya 2012, Palermo 2016, Tzetis 2001). This variant is reported as uncertain significance by multiple laboratories in ClinVar (Variation ID: 495928), and is found in the non-Finnish European population with an allele frequency of 0.031% (40/128,740 alleles) in the Genome Aggregation Database. The valine at codon 11 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Val11Ile variant is uncertain at this time. References: Maurya N et al. Association of CFTR gene mutation with bronchial asthma. Indian J Med Res. 2012 Apr;135(4):469-78. Palermo JJ et al. Genophenotypic Analysis of Pediatric Patients With Acute Recurrent and Chronic Pancreatitis. Pancreas. 2016 Oct;45(9):1347-52. Tzetis M et al. CFTR gene mutations--including three novel nucleotide substitutions--and haplotype background in patients with asthma, disseminated bronchiectasis and chronic obstructive pulmonary disease. Hum Genet. 2001 108(3):216-21. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 28, 2023	Variant summary: CFTR c.31G>A (p.Val11Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 250988 control chromosomes (gnomAD). This frequency is not higher than the maximum estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (0.013), allowing no conclusion about variant significance. The variant, c.31G>A, has been reported in the literature in individuals with various phenotypes including asthma, chronic pancreatitis, idiopathic azoospermia / oligozoospermia, and primary sclerosing cholangitis, all without strong evidence for causality (example, Tzetis_2001, Palermo_2016, Oud_2017, Werlin_2018). In addition, the variant was also reported in an asymptomatic individual along with p.Phe508del (Claustres_2017), in an individual reporting unspecified spectrum of CF (Schrijver_2005) and was found in trans with p.Phe508del during newborn screening (Skov_2019). 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. The following publications have been ascertained in the context of this evaluation (PMID: 22324837, 28603918, 22664493, 28801929, 27171515, 25735457, 16049310, 31682332, 11354633, 29807875). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as uncertain significance. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary pancreatitis

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Jan 07, 2022

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 03, 2022

- -

CFTR-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 31, 2024

The CFTR c.31G>A variant is predicted to result in the amino acid substitution p.Val11Ile. This variant has been reported in individuals with asthma, chronic pancreatitis, cystic fibrosis, primary sclerosing cholangitis, and male infertility (Tzetis et al. 2001. PubMed ID: 11354633; Palermo et al. 2016. PubMed ID: 27171515; Schrijver et al. 2005. PubMed ID: 15858154; Werlin et al. 2018. PubMed ID: 29807875; Table S4, Oud et al. 2017. PubMed ID: 28801929); however, additional details supporting pathogenicity were not provided. The individual with asthma who carried this variant also carried CFTR c.2T>C, which disrupts the start codon (Tzetis et al. 2001. PubMed ID: 11354633). This variant has also been detected in individuals who carry the common pathogenic variant c.1521_1523del (p.Phe508del) and are asymptomatic or considered healthy carriers (Claustres et al. 2017. PubMed ID: 28603918; Supporting Information Data, Skov et al. 2019. PubMed ID: 31682332). This variant is reported in 0.031% of alleles in individuals of European (non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Bronchiectasis with or without elevated sweat chloride 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

May 02, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.30

T;.;.;T;.

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.68

T;T;T;T;T

M_CAP

Benign

0.027

MetaRNN

Benign

0.094

T;T;T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

-0.92

N;.;.;.;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.45

PROVEAN

Benign

0.28

N;.;.;N;.

REVEL

Uncertain

0.45

Sift

Benign

0.60

T;.;.;T;.

Sift4G

Benign

0.40

T;.;.;T;.

Polyphen

0.0010

B;.;.;.;.

Vest4

0.64

MVP

0.88

MPC

0.0044

ClinPred

0.045

GERP RS

2.1

Varity_R

0.19

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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