NM_000492.4:c.3469-17T>C
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6BS2_Supporting
The NM_000492.4(CFTR):c.3469-17T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00085 in 1,612,446 control chromosomes in the GnomAD database, including 4 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 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.3469-17T>C | intron_variant | Intron 21 of 26 | ENST00000003084.11 | NP_000483.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000480 AC: 73AN: 152166Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000592 AC: 148AN: 249920Hom.: 1 AF XY: 0.000822 AC XY: 111AN XY: 135080
GnomAD4 exome AF: 0.000888 AC: 1297AN: 1460162Hom.: 4 Cov.: 31 AF XY: 0.000979 AC XY: 711AN XY: 726376
GnomAD4 genome AF: 0.000479 AC: 73AN: 152284Hom.: 0 Cov.: 32 AF XY: 0.000551 AC XY: 41AN XY: 74456
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:2
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The CFTR c.3469-17T>C variant has been reported in the published literature in individuals with cystic fibrosis (PMID: 7683952 (1993), 12815607 (2003), 28544683 (2017)) and CFTR-RD, including azoospermia (PMID: 20021716 (2009), 28456595 (2017)) as well as in unaffected individuals (PMID: 17890437 (2007)). The frequency of this variant in the general population, 0.0033 (100/30538 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect CFTR mRNA splicing . Based on the available information, we are unable to determine the clinical significance of this variant. -
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Also known as c.3601-17T>C, observed in individuals with cystic fibrosis, but additional information was not provided (Audrezet et al., 1993; Soltysova et al., 2018); In silico analysis supports that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 26847993, 28456595, 20021716, 10439967, 17890437, 18685558, 23503723, 25797027, 28544683, 10923036, 12815607, 34426522, 7683952) -
Cystic fibrosis Uncertain:1Benign:2
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This alteration is classified as 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. -
not specified Benign:3
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Variant summary: CFTR c.3469-17T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00059 in 250506 control chromosomes, predominantly at a frequency of 0.0033 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00059 vs 0.013), allowing no conclusion about variant significance. c.3469-17T>C has been reported in the literature as non-informative genotypes (second allele and/or phase not specified) in cohorts of individuals affected with Cystic Fibrosis, diffuse bronchiectasis and azoospermia (e.g. Audrezet_1993, Claustres_2000, Scotet_2003, Gallati_2009, Soltysova_2018, Vaidyanathan_2022) but it was also reported in healthy controls (e.g. Bergougnoux_2015). These report(s) do not provide unequivocal conclusions about a penetrant association of the variant with fulminant Cystic Fibrosis. The variant was found to co-occur with two other deleterious CFTR variants (c.1393-1G>A and c.5T_TG12) in at-least one specimen tested at our laboratory. The phase of this variant was not determined, however it provides supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 7683952, 25797027, 10923036, 18685558, 20021716, 28456595, 26847993, 17890437, 12815607, 28544683, 35857025, 23503723). ClinVar contains an entry for this variant (Variation ID: 53751). Based on the evidence outlined above, the variant was classified as likely benign. -
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Congenital bilateral aplasia of vas deferens from CFTR mutation Uncertain:1
PM2_Supporting+PM3_Supporting -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at