dbSNP rs78655421: CFTR:p.Arg117His (chr7-117530975-G-A) – ACMG Classification: Pathogenic (13 pts)

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 14P and 1B. PM1PM5PP2PP3PP5_Very_StrongBP4

The NM_000492.4(CFTR):c.350G>A(p.Arg117His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 1,613,574 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign 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. R117P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0015 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 5 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Pathogenic practice guideline P:43O:2

Conservation

PhyloP100: 9.52

Publications

694 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 13 ACMG points.

PM1

In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 20 uncertain in NM_000492.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-117530975-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 53764.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.

PP3

Multiple lines of computational evidence support a deleterious effect 9: BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

PP5

Variant 7-117530975-G-A is Pathogenic according to our data. Variant chr7-117530975-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 7109.Status of the report is practice_guideline, 4 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.1833263). . Strength limited to SUPPORTING due to the PP5.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.350G>A	p.Arg117His	missense	Exon 4 of 27	NP_000483.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CFTR	ENST00000003084.11	TSL:1 MANE Select	c.350G>A	p.Arg117His	missense	Exon 4 of 27	ENSP00000003084.6
CFTR	ENST00000699602.1		c.350G>A	p.Arg117His	missense	Exon 4 of 27	ENSP00000514471.1
CFTR	ENST00000889206.1		c.350G>A	p.Arg117His	missense	Exon 4 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes

AF:

0.00152

AC:

231

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00265

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00149

AC:

373

AN:

250954

AF XY:

0.00148

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000610

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00190

Gnomad NFE exome

AF:

0.00265

Gnomad OTH exome

AF:

0.000654

GnomAD4 exome

AF:

0.00220

AC:

3214

AN:

1461404

Hom.:

Cov.:

AF XY:

0.00213

AC XY:

1545

AN XY:

727012

show subpopulations

African (AFR)

AF:

0.000448

AC:

AN:

33462

American (AMR)

AF:

0.000694

AC:

AN:

44640

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00140

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00271

AC:

3017

AN:

1111726

Other (OTH)

AF:

0.00121

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

151

302

454

605

756

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

228

342

456

570

<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:

0.00152

AC:

231

AN:

152170

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

107

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.000579

AC:

AN:

41452

American (AMR)

AF:

0.000393

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00188

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00265

AC:

180

AN:

68030

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.00239

Hom.:

Bravo

AF:

0.00140

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.00152

AC:

185

EpiCase

AF:

0.00169

EpiControl

AF:

0.00190

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:practice guideline

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cystic fibrosis (18)

not provided (14)

CFTR-related disorder (2)

Congenital bilateral aplasia of vas deferens from CFTR mutation (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 (2)

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation (2)

Bronchiectasis with or without elevated sweat chloride 1 (1)

Obstructive azoospermia (1)

Pseudomonas aeruginosa, susceptibility to chronic infection by, in cystic fibrosis (1)

Respiratory ciliopathies including non-CF bronchiectasis (1)

ivacaftor response - Efficacy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.66

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.89

MetaRNN

Benign

0.18

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.1

PhyloP100

9.5

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-5.0

REVEL

Pathogenic

0.81

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.88

MVP

1.0

MPC

0.011

ClinPred

0.058

GERP RS

5.7

Varity_R

0.55

gMVP

0.92

Mutation Taster

=30/70

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over