Genetic Variant CFTR:p.Asp1152His (chr7-117614699-G-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 8P and 2B. PS3PM1PP2PP3BP4_Moderate

The NM_000492.4(CFTR):c.3454G>C(p.Asp1152His) variant causes a missense change. The variant allele was found at a frequency of 0.000398 in 1,610,026 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★). ClinVar reports functional evidence for this variant: "SCV000074908: Experimental studies have shown that this missense change affects CFTR function (PMID:9804160, 23891399, 25033378)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1152G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00032 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00041 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

drug response reviewed by expert panel P:42O:1

Conservation

PhyloP100: 5.26

Publications

216 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: Likely_pathogenic. The variant received 6 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000074908: Experimental studies have shown that this missense change affects CFTR function (PMID: 9804160, 23891399, 25033378).; SCV000916188: Functional studies on the p.Asp1152His variant showed chloride transport activity is 57.4% of the wild type (Van Goor et al. 2014). La Rusch et al. (2014) report that the p.Asp1152His variant causes a narrowing of the channel diameter which would affect conductance properties. The p.Asp1152His variant was shown to exhibit normal chloride function in HEK293 cells with significantly reduced bicarbonate permeability and conductance (LaRusch et al. 2014). Vankeerberghen et al. (1998) demonstrated in Xenopus oocytes that the p.Asp1152His variant did not alter the permeability sequence of the CFTR channels but led to whole cell cAMP activated chloride currents that were significantly reduced compared to wild type indicating that the variant interfere with the proper gating of the chloride channels.; SCV001181807: Functional in vitro studies found that cells carrying this pathogenic mutation retained the ability to conduct chloride (Sosnay PR et al. Nat. Genet. 2013 Oct; 45(10):1160-7).; SCV000329250: "In vitro functional studies indicated that the D1152H variant results in a protein whose chloride transport is approximately 57% that of wild-type" (VanGoor et al., 2014; LaRusch et al., 2014).; SCV000601100: "In addition, published functional studies demonstrated that this variant partially reduces chloride transport activity, affects proper channel gating, and reduces bicarbonate permeability (PMIDs: 32414100 (2020), 25033378 (2014), 23891399 (2014), 9804160 (1998))."; SCV006325071: Functional studies indicate that this sequence change has an effect on CFTR function (PMID: 9804160, 25033378).; SCV000603066: Functional characterization of the variant protein indicates a significant reduction in chloride and bicarbonate transport activity (LaRusch 2014, Sosnay 2013, Van Goor 2014, Vankeerberghen 1998).; SCV007097386: Functional assays demonstrate reduced but residual CFTR activity (PS3_moderate). PMID:25033378, PMID:25583415

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 21 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.

PP3

Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_noAF, Cadd, M_CAP, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.188137).

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.3454G>C	p.Asp1152His	missense	Exon 21 of 27	NP_000483.3
	CFTR-AS2	NR_199597.1		n.177+1530C>G		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CFTR	ENST00000003084.11	TSL:1 MANE Select	c.3454G>C	p.Asp1152His	missense	Exon 21 of 27	ENSP00000003084.6	P13569-1
CFTR	ENST00000699602.1		c.3448G>C	p.Asp1150His	missense	Exon 21 of 27	ENSP00000514471.1	A0A8V8TNH2
CFTR	ENST00000889206.1		c.3367G>C	p.Asp1123His	missense	Exon 20 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes

AF:

0.000316

AC:

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000515

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000398

AC:

100

AN:

250946

AF XY:

0.000361

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000869

Gnomad ASJ exome

AF:

0.00258

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000335

Gnomad OTH exome

AF:

0.000655

GnomAD4 exome

AF:

0.000407

AC:

593

AN:

1457986

Hom.:

Cov.:

AF XY:

0.000374

AC XY:

271

AN XY:

725492

show subpopulations

African (AFR)

AF:

0.000150

AC:

AN:

33350

American (AMR)

AF:

0.000828

AC:

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.00246

AC:

AN:

26060

East Asian (EAS)

AF:

0.00

AC:

AN:

39580

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86186

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53362

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.000411

AC:

456

AN:

1108770

Other (OTH)

AF:

0.000465

AC:

AN:

60246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

105

131

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000316

AC:

AN:

152040

Hom.:

Cov.:

AF XY:

0.000337

AC XY:

AN XY:

74280

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41398

American (AMR)

AF:

0.000262

AC:

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000515

AC:

AN:

67990

Other (OTH)

AF:

0.000479

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.000512

Hom.:

Bravo

AF:

0.000378

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000264

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000474

ClinVar

ClinVar submissions

Significance:drug response

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cystic fibrosis (16)

not provided (14)

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)

Bronchiectasis with or without elevated sweat chloride 1 (1)

Congenital bilateral aplasia of vas deferens from CFTR mutation (1)

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

Cystic fibrosis;C5924204:CFTR-related disorder (1)

Male infertility (1)

Melanoma-pancreatic cancer syndrome (1)

Obstructive azoospermia (1)

ivacaftor response - Efficacy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Uncertain

0.045

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.79

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.38

MutationAssessor

Uncertain

2.8

PhyloP100

5.3

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.7

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.013

Polyphen

0.57

Vest4

0.92

MVP

0.99

MPC

0.011

ClinPred

0.12

GERP RS

5.9

PromoterAI

-0.024

Neutral

(source)

Varity_R

0.71

gMVP

0.90

Mutation Taster

=3/97

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

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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