rs75647395

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000492.4(CFTR):c.3607A>G(p.Ile1203Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,216 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: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:10

Conservation

PhyloP100: 0.350

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13899153).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.3607A>G	p.Ile1203Val	missense_variant	22/27	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.3607A>G	p.Ile1203Val	missense_variant	22/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1
	ENST00000456270.1 linkuse as main transcript	n.66-11320T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000799

AC:

AN:

250372

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135266

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461216

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726906

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 07, 2022	The p.I1203V variant (also known as c.3607A>G), located in coding exon 22 of the CFTR gene, results from an A to G substitution at nucleotide position 3607. The isoleucine at codon 1203 is replaced by valine, an amino acid with highly similar properties. This variant was reported in a homozygous state in an infant with obstructive lung disease, airway colonization by Pseudomonas aeruginosa, and a positive sweat test (Fredj SH et al. Genet Test Mol Biomarkers, 2009 Oct;13:577-81). This amino acid position is not well conserved in available vertebrate species, and valine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 08, 2022	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1203 of the CFTR protein (p.Ile1203Val). This variant is present in population databases (rs75647395, gnomAD 0.007%). This missense change has been observed in individual(s) with cystic fibrosis (CF) and CF carried this combination of variants (PMID: 1376017, 19715466, 28546993; p.Ser1255*). ClinVar contains an entry for this variant (Variation ID: 53778). 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. 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, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 25, 2019	The CFTR c.3607A>G; p.Ile1203Val variant (rs75647395) is reported in the literature in several individuals with symptoms or a diagnosis of cystic fibrosis (Behar 2017, Cutting 1992, Fredj 2009). This variant has been reported to occur on the same chromosome as a pathogenic CFTR variant, p.Ser1255Ter (Cutting 1992). Indeed, a number of affected individuals in the literature or identified in testing at ARUP Laboratories carried both the p.Ile1203Val variant and p.Ser1255Ter (Behar 2017, Cutting 1992), although one affected individual with a homozygous p.Ile1203Val variant was reported without p.Ser1255Ter (Fredj 2009). The p.Ile1203Val variant is found on only two chromosomes (2/250372 alleles) in the Genome Aggregation Database. The valine at codon 1203 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Although available information does not strongly suggest that the p.Ile1203Val variant is disease-causing on its own, due to limited information, its clinical significance is uncertain at this time. References: Behar DM et al. Nationwide genetic analysis for molecularly unresolved cystic fibrosis patients in a multiethnic society: implications for preconception carrier screening. Mol Genet Genomic Med. 2017 Feb 19;5(3):223-236. Cutting GR et al. Analysis of four diverse population groups indicates that a subset of cystic fibrosis mutations occur in common among Caucasians. Am J Hum Genet. 1992 Jun;50(6):1185-94. Fredj SH et al. Cystic fibrosis transmembrane conductance regulator mutation spectrum in patients with cystic fibrosis in Tunisia. Genet Test Mol Biomarkers. 2009 Oct;13(5):577-81. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 23, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 28, 2022	BP2, PM2, PM3_supporting -

CFTR-related disorder

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 24, 2024	The CFTR c.3607A>G variant is predicted to result in the amino acid substitution p.Ile1203Val. This variant was reported in the homozygous state in an individual with cystic fibrosis (Fredj et al. 2009. PubMed ID: 19715466) and was identified in a cohort of individuals with cystic fibrosis (da Silva Filho et al. 2021. PubMed ID: 32819855). However, this variant was also reported to occur in cis with the p.Ser1255* variant in an African-American patient with symptoms diagnostic of cystic fibrosis (Cutting et al. 1992. PubMed ID: 1376017). This variant was also described in an affected individual who carried both p.Phe508del and p.Ser1255* (phase not determined, Behar et al. 2017. PubMed ID: 28546993). In ClinVar, multiple laboratories classify the c.3607A>G (p.Ile1203Val) variant as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/53778/). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 23, 2018	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 02, 2023

Variant summary: CFTR c.3607A>G (p.Ile1203Val) 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 8e-06 in 250372 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3607A>G has been reported in the literature in several individuals diagnosed with Cystic Fibrosis (e.g., Cutting_1992, Behar_2017, Fredj_2009, Hamouda_2020, daSilvaFilho_2021). At least two of the individuals carried a known pathogenic CFTR variant, c.3764C>A (p.Ser1255X) in cis (Cutting_1992, Behar_2017), providing supporting evidence for a benign role. However, the variant was also reported in the homozygous state in at least one individual with obstructive lung disease, airway colonization by Pseudomonas aeruginisa and a positive sweat test (67mM; e.g., Fredj_2009, Hamouda_2020). Mutational scanning by DGGE was utilized in this report, therefore the possibility of a missed mutation cannot be entirely ruled out. Therefore, these reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. This variant was identified in an internal specimen with the combination of c.1853T>C (classified as VUS-possibly pathogenic)/c.3607A>G/c.3764C>A (classified as Pathogenic). Although the phase was not determined at time of testing, the genotype appears similar to that reported in the literature. 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: 28546993, 1376017, 19715466, 33402933, 32819855). Six ClinVar submitters (evaluation after 2014) have cited the variant, and all submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant in isolation was classified as VUS-possibly benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

0.0084

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

8.5

DANN

Benign

0.91

DEOGEN2

Benign

0.30

T;.;.;T;.

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.68

T;T;T;T;T

M_CAP

Benign

0.081

MetaRNN

Benign

0.14

T;T;T;T;T

MetaSVM

Benign

-0.60

MutationAssessor

Benign

0.90

L;.;.;.;.

MutationTaster

Benign

0.99

N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

0.11

N;.;.;N;.

REVEL

Uncertain

0.48

Sift

Benign

0.56

T;.;.;T;.

Sift4G

Benign

0.62

T;.;.;T;.

Polyphen

0.0

B;.;.;.;.

Vest4

0.69

MVP

0.92

MPC

0.0044

ClinPred

0.058

GERP RS

4.3

Varity_R

0.10

gMVP

0.50

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

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