rs397508699

Variant names:

• chr7-117665547-G-A
• rs397508699
• NM_000492.4:c.4225G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-117665547-G-A
• chr7-117665547-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP2 PP3_Moderate PP5

The NM_000492.4(CFTR):​c.4225G>A​(p.Glu1409Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000745 in 1,611,338 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:6 O:1
• Conservation: PhyloP100: 9.15
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• cystic fibrosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
• congenital bilateral absence of vas deferens

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary chronic pancreatitis

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 197 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: -3.1397 (below the threshold of 3.09). Trascript score misZ: -1.0868 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary chronic pancreatitis, cystic fibrosis, congenital bilateral absence of vas deferens.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938
• PP5: Variant 7-117665547-G-A is Pathogenic according to our data. Variant chr7-117665547-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 53923.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.4225G>A	p.Glu1409Lys	missense_variant	Exon 26 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.4225G>A	p.Glu1409Lys	missense_variant	Exon 26 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250766 AF XY: 0.00000738

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1459146 Hom.: 0 Cov.: 29 AF XY: 0.00000826 AC XY: 6 AN XY: 726064

African (AFR) AF: 0.00 AC: 0 AN: 33412

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.000177 AC: 7 AN: 39576

South Asian (SAS) AF: 0.00 AC: 0 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1109730

Other (OTH) AF: 0.00 AC: 0 AN: 60274

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152192 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74344

African (AFR) AF: 0.00 AC: 0 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000186 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:6 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:2 Uncertain:4 Other:1

Dec 06, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CFTR c.4225G>A (p.Glu1409Lys) results in a conservative amino acid change located in the ATPase domain (IPR003593) 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 4e-06 in 250766 control chromosomes. c.4225G>A has been reported in the literature in compound heterozygous individuals affected with Cystic Fibrosis (Girardet_2015, Mota_2018). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 11.52% of normal activity in an in vitro cellular assay (Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 38388235, 33572515, 34740355, 32357917, 20059485, 24762087, 30232781, 25735457, 18556774, 26277102). ClinVar contains an entry for this variant (Variation ID: 53923). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Nov 05, 2018

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 05, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E1409K variant (also known as c.4225G>A), located in coding exon 26 of the CFTR gene, results from a G to A substitution at nucleotide position 4225. The glutamic acid at codon 1409 is replaced by lysine, an amino acid with similar properties. This variant was identified in conjunction with p.F508del in a Brazilian individual with elevated sweat chloride levels, respiratory symptoms, and steatorrhea; however, the phase was not provided (Mota LR et al. Mol. Biol. Rep., 2018 Dec;45:2045-2051). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

Dec 12, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Nov 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1409 of the CFTR protein (p.Glu1409Lys). This variant is present in population databases (rs397508699, gnomAD 0.0009%). This missense change has been observed in individual(s) with CFTR-related conditions (PMID: 30232781; external communication). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 53923). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

not provided Uncertain:1

Aug 08, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.4225G>A; p.Glu1409Lys variant (rs397508699) is reported in the Cystic Fibrosis Mutation database in an individual with a CFTR-related disorder who also carried a pathogenic CFTR variant (see link). The p.Glu1409Lys protein alteration is also reported in individuals with cystic fibrosis, but it is unclear if this is the same nucleotide variant or if other CFTR variants are present or not (Mota 2018, Schrijver 2008). This variant is reported in ClinVar (Variation ID: 53923), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The glutamic acid at codon 1409 is moderately conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: possibly damaging) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the p.Glu1409Lys variant is uncertain at this time. References: Link to Cystic Fibrosis Mutation database: http://www.genet.sickkids.on.ca/cftr/Home.html Mota LR et al. Description of rare mutations and a novel variant in Brazilian patients with Cystic Fibrosis: a case series from a referral center in the Bahia State. Mol Biol Rep. 2018 Dec;45(6):2045-2051. Schrijver I et al. Multiplex ligation-dependent probe amplification identification of whole exon and single nucleotide deletions in the CFTR gene of Hispanic individuals with cystic fibrosis. J Mol Diagn. 2008 Jul;10(4):368-75.

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

Sep 25, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;T;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.57
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	0.56	N;.;.
PhyloP100		9.2
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.4	N;N;.
Sift	Benign	0.10	T;T;.
Sift4G	Uncertain	0.0090	D;D;.
Vest4		0.96
ClinPred		0.81	D
GERP RS		5.7
Varity_R		0.64
gMVP		0.68
Mutation Taster		=10/90	disease causing

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

Other links and lift over

dbSNP: rs397508699; hg19: chr7-117305601;