rs74767530

chr7-117627537-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000492.4(CFTR):c.3484C>T(p.Arg1162Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000459 in 1,612,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: CFTR NM_000492.4 stop_gained
• Clinical Significance: Pathogenic practice guideline P:24 O:1
• Conservation: PhyloP100: 1.53

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-117627537-C-T is Pathogenic according to our data. Variant chr7-117627537-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7137.Status of the report is practice_guideline, 4 stars. Variant chr7-117627537-C-T is described in Lovd as [Pathogenic]. Variant chr7-117627537-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.3484C>T	p.Arg1162Ter	stop_gained	22/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.3484C>T	p.Arg1162Ter	stop_gained	22/27	1	NM_000492.4	P2
	ENST00000456270.1	n.66-11197G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152030 Hom.: 0 Cov.: 32

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: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000559 AC: 14 AN: 250612 Hom.: 0 AF XY: 0.0000738 AC XY: 10 AN XY: 135436

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 SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000530

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000459 AC: 67 AN: 1460898 Hom.: 0 Cov.: 31 AF XY: 0.0000482 AC XY: 35 AN XY: 726736

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000896

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152030 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74252

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000855 Hom.: 0

Bravo AF: 0.0000604

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:24 Other:1

Revision: practice guideline

Submissions by phenotype

Cystic fibrosis Pathogenic:11 Other:1

Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	This sequence change creates a premature translational stop signal (p.Arg1162*) in the CFTR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs74767530, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (CF) and is included in the American College of Medical Genetics (ACMG) panel of CF variants (PMID: 15371902, 23974870). ClinVar contains an entry for this variant (Variation ID: 7137). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 04, 2023	The p.R1162* pathogenic mutation (also known as c.3484C>T), located in coding exon 22 of the CFTR gene, results from a C to T substitution at nucleotide position 3484. This changes the amino acid from an arginine to a stop codon within coding exon 22. This mutation has been reported in the homozygous state in nine individuals with pancreatic insufficiency and mild to moderate pulmonary symptoms (Gasparini P et al. J. Med. Genet., 1992 Aug;29:558-62). This pathogenic mutation is associated with elevated sweat chloride levels, pancreatic insufficiency, and decreased lung function (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7; Shahin WA et al. Springerplus, 2016 May;5:686). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.3484C>T;p.(Arg1162*) variant creates a premature translational stop signal in the CFTR gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant(ClinVar ID: 7137; PMID: 20301428; 21416780; 15994263; 11101688; 20301428; 21811577; 7526685) - PS4. The variant is present at low allele frequencies population databases (rs74767530 – gnomAD 0.004604%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg1162*) was detected in trans with a pathogenic variant(PMID: 21811577) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, practice guideline	curation	American College of Medical Genetics and Genomics (ACMG)	Mar 03, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). The variant has been reported multiple times as an established pathogenic/likely pathogenic variant (ClinVar ID: VCV000007137, PMID:2045102). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000057, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 12, 2019	NM_000492.3(CFTR):c.3484C>T(R1162*) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of this disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.3484C>T(R1162*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1992	- -

not provided Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 04, 2020	The CFTR c.3484C>T; p.Arg1162Ter variant (rs74767530) has been reported in patients diagnosed with cystic fibrosis, and is often associated with pancreatic insufficiency (Gasparini 1991, Gasparini 1992, Ooi 2012, Sosnay 2013, CFTR2 database). This variant is reported in ClinVar (Variation ID: 7137), and is found in the general population with an overall allele frequency of 0.0057% (16/281996 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the p.Arg1162Ter variant is considered to be pathogenic. References: CFTR2 database: http://cftr2.org/ Gasparini P et al. The search for south European cystic fibrosis mutations: identification of two new mutations, four variants, and intronic sequences. Genomics. 1991; 10(1):193-200. Gasparini P et al. Nine cystic fibrosis patients homozygous for the CFTR nonsense mutation R1162X have mild or moderate lung disease. J Med Genet. 1992; 29(8):558-62. Ooi C. et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012; 11(5):355-62. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013; 45(10):1160-7. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Aug 28, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 05, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 17, 2022	- -

CFTR-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 14, 2024	The CFTR c.3484C>T variant is predicted to result in premature protein termination (p.Arg1162*). This variant has been repeatedly reported to be causative for cystic fibrosis (see for example Gasparini et al. 1991. PubMed ID: 2045102; Sosnay et al. 2013. PubMed ID: 23974870). This variant is reported in 0.023% of alleles in individuals of South Asian descent in gnomAD. Nonsense variants in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 14, 2018

Variant summary: CFTR c.3484C>T (p.Arg1162X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 5.4e-05 in 276330 control chromosomes. The c.3484C>T variant has been reported in the literature in numerous individuals affected with Cystic Fibrosis and is considered a common pathogenic mutation (see e.g. Sosnay 2013, Gasparini 1991). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence, which showed the lack of full length CFTR protein and improper localization of the truncated form at the plasma membrane in cells from a homozygous patient (Sorio 2011). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 04, 2021

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.62
Cadd	Pathogenic	39
Dann	Uncertain	1.0
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.97	D
MutationTaster	Benign	1.0	A;A
Vest4		0.95
GERP RS		3.8

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

LitVar

Other links and lift over

dbSNP: rs74767530; hg19: chr7-117267591;