Genetic Variant CFTR:p.Arg560Thr (chr7-117587833-G-C) – ACMG Classification: Pathogenic (21 pts)

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS3PM1PM5PP2PP3_StrongPP5_Very_Strong

The NM_000492.4(CFTR):c.1679G>C(p.Arg560Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000656 in 1,554,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 15/26 in silico tools predict a damaging outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★★). ClinVar reports functional evidence for this variant: "SCV000074427: Experimental studies have shown that this missense change affects CFTR function (PMID:23974870).; SCV001470740: Functional analyses of this variant demonstrate mRNA splicing defects and a marked reduction in translation of mature CFTR protein (Kerem 1990, van Goor 2014). PMID:2236053 PMID:23891399; SCV002714483: Functional in vitro studies found that cells carrying this pathogenic mutation had no to very little chloride conduction; in addition, this pathogenic mutation is associated with high sweat chloride levels and pancreatic insufficiency Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7; Van Goor F et al. J. Cyst. Fibros., 2014 Jan;13:29-36).; SCV000917179: studies assessing the variant effect at the protein level have shown a defective glycosylation/maturation and chloride conductance (Van Goor 2013, Sosnay 2013).; SCV005900693: Functional studies have demonstrated that the c.1679G>C (p.Arg560Thr) variant results in altered mRNA splicing, decreased levels of translated mRNA, and impaired protein function (PMID:2236053, 23974870, 23891399).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R560S) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000071 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic practice guideline P:21O:1

Conservation

PhyloP100: 8.82

Publications

107 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 21 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000074427: Experimental studies have shown that this missense change affects CFTR function (PMID: 23974870).; SCV001470740: Functional analyses of this variant demonstrate mRNA splicing defects and a marked reduction in translation of mature CFTR protein (Kerem 1990, van Goor 2014). PMID: 2236053 PMID: 23891399; SCV002714483: Functional in vitro studies found that cells carrying this pathogenic mutation had no to very little chloride conduction; in addition, this pathogenic mutation is associated with high sweat chloride levels and pancreatic insufficiency Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7; Van Goor F et al. J. Cyst. Fibros., 2014 Jan;13:29-36).; SCV000917179: studies assessing the variant effect at the protein level have shown a defective glycosylation/maturation and chloride conductance (Van Goor 2013, Sosnay 2013).; SCV005900693: Functional studies have demonstrated that the c.1679G>C (p.Arg560Thr) variant results in altered mRNA splicing, decreased levels of translated mRNA, and impaired protein function (PMID: 2236053, 23974870, 23891399).

PM1

In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 20 uncertain in NM_000492.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-117590353-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 53339.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

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 7-117587833-G-C is Pathogenic according to our data. Variant chr7-117587833-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 7113.Status of the report is practice_guideline, 4 stars.

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.1679G>C	p.Arg560Thr	missense splice_region	Exon 12 of 27	NP_000483.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CFTR	ENST00000003084.11	TSL:1 MANE Select	c.1679G>C	p.Arg560Thr	missense splice_region	Exon 12 of 27	ENSP00000003084.6	P13569-1
CFTR	ENST00000699602.1		c.1679G>C	p.Arg560Thr	missense splice_region	Exon 12 of 27	ENSP00000514471.1	A0A8V8TNH2
CFTR	ENST00000889206.1		c.1679G>C	p.Ser560Thr	missense splice_region	Exon 12 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152132

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000240

AC:

AN:

250518

AF XY:

0.00000739

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:

0.0000530

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000706

AC:

AN:

1402616

Hom.:

Cov.:

AF XY:

0.0000641

AC XY:

AN XY:

701596

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32232

American (AMR)

AF:

0.00

AC:

AN:

44522

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25724

East Asian (EAS)

AF:

0.00

AC:

AN:

39322

South Asian (SAS)

AF:

0.00

AC:

AN:

85100

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53354

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5672

European-Non Finnish (NFE)

AF:

0.0000813

AC:

AN:

1058278

Other (OTH)

AF:

0.000223

AC:

AN:

58412

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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:

0.0000197

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.0000483

Hom.:

Bravo

AF:

0.0000264

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:practice guideline

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cystic fibrosis (10)

CFTR-related disorder (4)

not provided (4)

Bronchiectasis with or without elevated sweat chloride 1 (1)

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)

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.98

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.76

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

PhyloP100

8.8

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-5.6

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.98

MVP

1.0

MPC

0.014

ClinPred

1.0

GERP RS

5.3

Varity_R

1.0

gMVP

0.99

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.92

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.92

Position offset: 0

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