7-117591968-A-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM5PP2PP3_StrongPP5_Very_Strong

The NM_000492.4(CFTR):c.1801A>T(p.Ile601Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000752 in 1,595,260 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 Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I601L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:3O:1

Conservation

PhyloP100: 4.38

Publications

8 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 19 uncertain in NM_000492.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-117591969-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 53392.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, 0.981

PP5

Variant 7-117591968-A-T is Pathogenic according to our data. Variant chr7-117591968-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 53391.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.1801A>T	p.Ile601Phe	missense_variant	Exon 14 of 27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 link	c.1801A>T	p.Ile601Phe	missense_variant	Exon 14 of 27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000429

AC:

AN:

233316

AF XY:

0.00

show subpopulations

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:

0.00000920

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000693

AC:

AN:

1442986

Hom.:

Cov.:

AF XY:

0.00000558

AC XY:

AN XY:

717260

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32180

American (AMR)

AF:

0.00

AC:

AN:

39972

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25260

East Asian (EAS)

AF:

0.00

AC:

AN:

39598

South Asian (SAS)

AF:

0.00

AC:

AN:

81410

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53048

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5640

European-Non Finnish (NFE)

AF:

0.00000904

AC:

AN:

1106338

Other (OTH)

AF:

0.00

AC:

AN:

59540

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

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:

0.0000131

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41564

American (AMR)

AF:

0.00

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2112

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

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

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:2Other:1

May 20, 2021

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.1801A>T (p.Ile601Phe) results in a non-conservative amino acid change located in the ABC transporter-like 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 4.3e-06 in 233316 control chromosomes. c.1801A>T has been reported in the literature in individuals affected with CFTR-Related Diseases (CFTR-RD), including at least one patient with pancreatic sufficient CF and one patient with CBAVD (Vankeerberghen_1998, Steiner_2011). The variant has also been reported in 5 patients in the CFTR2 database, and was reported in the CFTR-France database in 2 patients with CF and 4 patients with CFTR-RD. At least one functional study reported that the variant gave rise to a protein that was aberrantly processed, resulting in the absence of sufficient CFTR protein at the cell surface (Vankeerberghen_1998). The CFTR2 and CFTR-France databases both report the variant as pathogenic for CF and/or CFTR-RD. However, the working group of the French CF society cited the variant in recently published guidelines as "a mutation of unproved or uncertain clinical relevance" (Sermet-Gaudelus_2017). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jan 10, 2020

CFTR2

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:research

- -

Cystic fibrosis;C5924204:CFTR-related disorder

Pathogenic:1

Jan 29, 2018

CFTR-France

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.87

D;.;T;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

0.85

MutationAssessor

Uncertain

2.5

M;.;.;.

PhyloP100

4.4

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.7

D;.;D;.

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0020

D;.;D;.

Sift4G

Uncertain

0.0090

D;.;D;.

Polyphen

1.0

D;.;.;.

Vest4

0.73

MutPred

0.91

Loss of MoRF binding (P = 0.1281);.;.;.;

MVP

1.0

MPC

0.0047

ClinPred

0.98

GERP RS

5.5

Varity_R

0.84

gMVP

0.97

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.23

Position offset: -34

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