7-117559629-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 5P and 4B. PM1PM5PP2BP4_Strong

The NM_000492.4(CFTR):c.1558G>A(p.Val520Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000114 in 1,613,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. V520F) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:18B:1

Conservation

PhyloP100: 4.96

Publications

60 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: Uncertain_significance. The variant received 1 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 25 uncertain in NM_000492.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-117559629-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 7150.Status of the report is reviewed_by_expert_panel, 3 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.051140845).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000492.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.1558G>A	p.Val520Ile	missense	Exon 11 of 27	NP_000483.3
	CFTR-AS1	NR_149084.1		n.221+1104C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CFTR	ENST00000003084.11	TSL:1 MANE Select	c.1558G>A	p.Val520Ile	missense	Exon 11 of 27	ENSP00000003084.6	P13569-1
CFTR	ENST00000699602.1		c.1558G>A	p.Val520Ile	missense	Exon 11 of 27	ENSP00000514471.1	A0A8V8TNH2
CFTR	ENST00000889206.1		c.1558G>A	p.Val520Ile	missense	Exon 11 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000147

AC:

AN:

251102

AF XY:

0.0000810

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000979

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000101

AC:

148

AN:

1460978

Hom.:

Cov.:

AF XY:

0.0000784

AC XY:

AN XY:

726852

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33450

American (AMR)

AF:

0.000179

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.000909

AC:

AN:

39614

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53232

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00000900

AC:

AN:

1111480

Other (OTH)

AF:

0.00139

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

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:

0.000237

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.000506

AC:

AN:

41524

American (AMR)

AF:

0.000262

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00155

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67978

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

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:

0.000258

Hom.:

Bravo

AF:

0.000264

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000157

AC:

Asia WGS

AF:

0.00375

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cystic fibrosis (7)

not provided (6)

CFTR-related disorder (2)

Hereditary pancreatitis (2)

Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.052

BayesDel_noAF

Pathogenic

0.22

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

Eigen

Benign

0.065

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.38

MetaRNN

Benign

0.051

MetaSVM

Uncertain

0.047

MutationAssessor

Benign

1.4

PhyloP100

5.0

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.89

REVEL

Uncertain

0.58

Sift

Benign

0.047

Sift4G

Benign

0.064

Polyphen

0.063

Vest4

0.74

MVP

0.97

MPC

0.011

ClinPred

0.022

GERP RS

5.5

Varity_R

0.58

gMVP

0.85

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over