7-117627538-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1PP2

The NM_000492.4(CFTR):c.3485G>T(p.Arg1162Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000789 in 1,613,148 control chromosomes in the GnomAD database, including 1 homozygotes. 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. R1162Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00067 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00080 ( 1 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:9B:5O:1

Conservation

PhyloP100: 8.89

Publications

44 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: Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Laboratory for Molecular Medicine
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: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 24 uncertain in NM_000492.4

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.

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.3485G>T	p.Arg1162Leu	missense	Exon 22 of 27	NP_000483.3
	CFTR-AS2	NR_199597.1		n.66-11198C>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CFTR	ENST00000003084.11	TSL:1 MANE Select	c.3485G>T	p.Arg1162Leu	missense	Exon 22 of 27	ENSP00000003084.6	P13569-1
CFTR	ENST00000699602.1		c.3479G>T	p.Arg1160Leu	missense	Exon 22 of 27	ENSP00000514471.1	A0A8V8TNH2
CFTR	ENST00000889206.1		c.3398G>T	p.Arg1133Leu	missense	Exon 21 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes

AF:

0.000671

AC:

102

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000787

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00122

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000678

AC:

170

AN:

250616

AF XY:

0.000628

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00128

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000801

AC:

1170

AN:

1460930

Hom.:

Cov.:

AF XY:

0.000812

AC XY:

590

AN XY:

726762

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33436

American (AMR)

AF:

0.000291

AC:

AN:

44642

Ashkenazi Jewish (ASJ)

AF:

0.000651

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39634

South Asian (SAS)

AF:

0.00

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.000187

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000983

AC:

1093

AN:

1111396

Other (OTH)

AF:

0.000530

AC:

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

114

171

228

285

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

104

130

<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:

0.000670

AC:

102

AN:

152218

Hom.:

Cov.:

AF XY:

0.000578

AC XY:

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41544

American (AMR)

AF:

0.000786

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00122

AC:

AN:

67998

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

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:

0.00136

Hom.:

Bravo

AF:

0.000797

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000675

AC:

EpiCase

AF:

0.00153

EpiControl

AF:

0.00142

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

Cystic fibrosis (5)

CFTR-related disorder (3)

Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 (2)

not specified (2)

Obstructive azoospermia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.83

MetaRNN

Uncertain

0.44

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.2

PhyloP100

8.9

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-6.0

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.98

Vest4

0.97

MVP

1.0

MPC

0.015

ClinPred

0.15

GERP RS

5.8

Varity_R

0.94

gMVP

0.98

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over