rs34911792
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2
The NM_000492.4(CFTR):c.3705T>G(p.Ser1235Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00782 in 1,611,572 control chromosomes in the GnomAD database, including 76 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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CFTR | NM_000492.4 | c.3705T>G | p.Ser1235Arg | missense_variant | Exon 22 of 27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00566 AC: 861AN: 152150Hom.: 5 Cov.: 32
GnomAD3 exomes AF: 0.00497 AC: 1235AN: 248242Hom.: 4 AF XY: 0.00505 AC XY: 678AN XY: 134318
GnomAD4 exome AF: 0.00805 AC: 11749AN: 1459304Hom.: 71 Cov.: 32 AF XY: 0.00792 AC XY: 5747AN XY: 726034
GnomAD4 genome AF: 0.00565 AC: 861AN: 152268Hom.: 5 Cov.: 32 AF XY: 0.00560 AC XY: 417AN XY: 74448
ClinVar
Submissions by phenotype
Cystic fibrosis Uncertain:2Benign:7
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This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
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not specified Benign:5
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Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
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The p.Ser1235Arg variant in CFTR is classified as benign because it has been ide ntified in 0.9% (87/10124) of Ashkenazi Jewish chromosomes and 0.7% (939/125536) of European chromosomes, including 4 homozygotes, by gnomAD (http://gnomad.broa dinstitute.org). ACMG/AMP Criteria applied: BA1. -
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not provided Uncertain:1Benign:2
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CFTR: BS2 -
The CFTR c.3705T>G; p.Ser1235Arg variant (rs34911792) is historically considered to be mildly pathogenic due to its prevalence in patients diagnosed with mild respiratory disorders (Rene 2011) or chronic pancreatitis (Hamoir 2013, Steiner 2011, Weiss 2005). However, genotype-phenotype studies indicate that the variant is observed at similar frequencies between affected and asymptomatic individuals (LaRusch 2014, Monaghan 2000, Rene 2011, Sosnay 2013). Functional studies also indicate no defect in CFTR maturation or chloride transport activity (Sosnay 2013, Van Goor 2014). The variant is listed in ClinVar (Variation ID: 35872) and is observed in the general population at an overall frequency of 0.5% (1,409/279,632 alleles, including 4 homozygotes) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.531). Current evidence indicates that this variant, when present with a pathogenic CFTR variant on the opposite chromosome, is not associated with classic cystic fibrosis. However, it remains uncertain whether it may contribute to the clinical phenotype in individuals with milder CFTR-related disease (e.g., an isolated presentation of pancreatitis, congenital bilateral absence of the vas deferens, or mild lung disease). References: Hamoir C et al. Clinical and morphological characteristics of sporadic genetically determined pancreatitis as compared to idiopathic pancreatitis: higher risk of pancreatic cancer in CFTR variants. Digestion. 2013; 87(4):229-39. PMID: 23751316. LaRusch J et al. Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis. PLoS Genet. 2014; 10(7):e1004376. PMID: 25033378. Monaghan K et al. Frequency and clinical significance of the S1235R mutation in the cystic fibrosis transmembrane conductance regulator gene: results from a collaborative study. Am J Med Genet. 2000; 95(4):361-5. PMID: 11186891. Rene C et al. p.Ser1235Arg should no longer be considered as a cystic fibrosis mutation: results from a large collaborative study. Eur J Hum Genet. 2011; 19(1):36-42. PMID: 20717170. 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. PMID: 23974870. Steiner B et al. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2011; 32(8):912-20. PMID: 21520337. Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014; 13(1):29-36. PMID: 23891399. Weiss F et al. Complete cystic fibrosis transmembrane conductance regulator gene sequencing in patients with idiopathic chronic pancreatitis and controls. Gut. 2005; 54(10):1456-60. PMID: 15987793. -
Obstructive azoospermia Pathogenic:1
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CFTR-related disorder Uncertain:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Congenital bilateral aplasia of vas deferens from CFTR mutation Uncertain:1
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Hereditary pancreatitis Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at