rs1554395370

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5

The NM_000492.4(CFTR):c.3794G>A(p.Gly1265Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,406 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. G1265V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 9.42

Publications

0 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 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)

CFTR links:

ENSG00000083622 (HGNC:40145):

ENSG00000083622 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 19 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 chr7-117642513-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1706052.Status of the report is criteria_provided_single_submitter, 1 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, 0.953

PP5

Variant 7-117642514-G-A is Pathogenic according to our data. Variant chr7-117642514-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 840799.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.3794G>A	p.Gly1265Glu	missense_variant	Exon 23 of 27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730
CFTR-AS2	NR_199597.1 link	n.65+4837C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 link	c.3794G>A	p.Gly1265Glu	missense_variant	Exon 23 of 27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461406

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726982

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33456

American (AMR)

AF:

0.00

AC:

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39640

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111738

Other (OTH)

AF:

0.00

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000370

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:2

Dec 16, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. This variant has not been reported in the literature in individuals with CFTR-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with glutamic acid at codon 1265 of the CFTR protein (p.Gly1265Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. -

Sep 16, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Congenital bilateral aplasia of vas deferens from CFTR mutation

Pathogenic:1

Nov 26, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Criteria applied: PM5,PP3_MOD,PM2_SUP,PM3_SUP; Identified as compound heterozygous with NM_000492.4:c.350G>A -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;D;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.95

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.9

H;.;.

PhyloP100

9.4

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-6.1

D;D;.

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;D;.

Sift4G

Uncertain

0.0030

D;D;.

Polyphen

1.0

D;.;.

Vest4

0.89

MVP

1.0

MPC

0.015

ClinPred

1.0

GERP RS

5.2

Varity_R

0.98

gMVP

0.98

Mutation Taster

=12/88

disease causing

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over