7-117548795-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM5PP2PP3_ModeratePP5

The NM_000492.4(CFTR):c.1364C>T(p.Ala455Val) variant causes a missense change. The variant allele was found at a frequency of 0.000095 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A455E) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000073 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000097 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:7

Conservation

PhyloP100: 7.18

Publications

209 publications found

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:

CFTR-AS1 (HGNC:40144): (CFTR antisense RNA 1)

CFTR-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 23 uncertain in NM_000492.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-117548795-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 7111.Status of the report is practice_guideline, 4 stars.

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, 0.874

PP5

Variant 7-117548795-C-T is Pathogenic according to our data. Variant chr7-117548795-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 411125.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.1364C>T	p.Ala455Val	missense_variant	Exon 10 of 27	ENST00000003084.11	NP_000483.3
CFTR-AS1	NR_149084.1 link	n.222-6256G>A		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 link	c.1364C>T	p.Ala455Val	missense_variant	Exon 10 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes

AF:

0.0000732

AC:

AN:

150274

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000245

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000200

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000211

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000889

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000574

AC:

AN:

243858

AF XY:

0.0000606

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000294

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000553

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000640

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000972

AC:

141

AN:

1450524

Hom.:

Cov.:

AF XY:

0.0000887

AC XY:

AN XY:

721354

show subpopulations

African (AFR)

AF:

0.0000302

AC:

AN:

33156

American (AMR)

AF:

0.0000455

AC:

AN:

43980

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25940

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39328

South Asian (SAS)

AF:

0.000117

AC:

AN:

85442

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52950

Middle Eastern (MID)

AF:

0.000349

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.000105

AC:

116

AN:

1104102

Other (OTH)

AF:

0.000150

AC:

AN:

59894

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000732

AC:

AN:

150274

Hom.:

Cov.:

AF XY:

0.0000546

AC XY:

AN XY:

73246

show subpopulations

African (AFR)

AF:

0.0000245

AC:

AN:

40890

American (AMR)

AF:

0.000200

AC:

AN:

15000

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3454

East Asian (EAS)

AF:

0.00

AC:

AN:

5136

South Asian (SAS)

AF:

0.000211

AC:

AN:

4732

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10292

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.0000889

AC:

AN:

67488

Other (OTH)

AF:

0.00

AC:

AN:

2062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:2Uncertain:3

Apr 10, 2025

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.A455V variant (also known as c.1364C>T), located in coding exon 10 of the CFTR gene, results from a C to T substitution at nucleotide position 1364. The alanine at codon 455 is replaced by valine, an amino acid with similar properties. This variant has been detected with a pathogenic CFTR mutation in an individual who was diagnosed with cystic fibrosis in adulthood (Nick JA et al. Am. J. Respir. Crit. Care Med., 2010 Sep;182:614-26). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Jul 22, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 16, 2019

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 455 of the CFTR protein (p.Ala455Val). 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 clinical features of CFTR-related conditions (PMID: 15371908, 20448091). ClinVar contains an entry for this variant (Variation ID: 411125). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CFTR protein function. This variant disrupts the p.Ala455 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23974870). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Mar 29, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:2

Oct 06, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 13, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Jan 06, 2025

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CFTR c.1364C>T (p.Ala455Val) results in a non-conservative amino acid change located in the ABC transporter-like domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.7e-05 in 243858 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (5.7e-05 vs 0.013), allowing no conclusion about variant significance. c.1364C>T has been reported in the literature in individuals undergoing carrier screening/clinical testing for Cystic Fibrosis (example, Buyse_2004, Strom_2003, Archibald_2018) and as a compound heterozygous genotype with another pathogenic CFTR variant in at-least one pancreatically sufficient individual in a cohort of CF patients over age 40 years (example, Nick_2010). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. A different variant affecting the same codon has been classified as pathogenic by our lab (c.1364C>A, p.Ala455Glu), supporting the critical relevance of codon 455 to CFTR protein function. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately (52.35)% of normal chloride channel conductance relative to wild type (e.g., Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 29261177, 15371908, 20448091, 12544470, 37628659, 38388235). ClinVar contains an entry for this variant (Variation ID: 411125). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

CFTR-related disorder

Uncertain:1

Dec 04, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The CFTR c.1364C>T variant is predicted to result in the amino acid substitution p.Ala455Val. This variant has been reported in individuals undergoing CFTR testing (Buyse et al. 2004. PubMed ID: 15371908; Archibald et al 2018. PubMed ID: 29261177); however, further evidence of pathogenicity was not provided. This variant, along with a nonsense CFTR variant, has also been reported in an individual diagnosed with cystic fibrosis in adulthood (Table E1, Nick JA et al. 2010. PubMed ID: 20448091). An alternative missense variant at the same amino acid position (i.e. p.Ala455Glu) is an established pathogenic variant (Sosnay et al. 2013. PubMed ID: 23974870). The c.1364C>T (p.Ala455Val) variant is reported in 0.017% of alleles in individuals of South Asian descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

D;D

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

D;D

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Pathogenic

0.80

MutationAssessor

Benign

0.98

L;.

PhyloP100

7.2

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-2.5

D;D

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.0070

D;D

Polyphen

1.0

D;.

Vest4

0.74

MutPred

0.84

Loss of catalytic residue at Q452 (P = 0.103);.;

MVP

1.0

MPC

0.0041

ClinPred

0.25

GERP RS

4.8

Varity_R

0.66

gMVP

0.97

Mutation Taster

=10/90

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over