rs1057516401
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000492.4(CFTR):c.4300_4301dup(p.Ser1435GlyfsTer14) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,908 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. N1432N) has been classified as Likely benign.
Frequency
Consequence
NM_000492.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.4300_4301dup | p.Ser1435GlyfsTer14 | frameshift_variant | 27/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.4300_4301dup | p.Ser1435GlyfsTer14 | frameshift_variant | 27/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250878Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135594
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461740Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727154
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74334
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 09, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects CFTR function (PMID: 30444886). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 370324). This variant is also known as 4428insGA and 4296_4297insGA. This premature translational stop signal has been observed in individual(s) with CFTR-related conditions (PMID: 11101688, 30548586). This variant is present in population databases (rs397508709, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Ser1435Glyfs*14) in the CFTR gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 46 amino acid(s) of the CFTR protein. - |
Pathogenic, reviewed by expert panel | research | CFTR2 | Mar 17, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 14, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | curation | Institute of Human Genetics, University of Leipzig Medical Center | Sep 05, 2022 | This variant was identified in 2 unrelated patients with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PVS1_MOD, PS3_SUP, PM2_SUP, PM3_STR, PP4 - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Nov 05, 2018 | - - |
Cystic fibrosis;na:CFTR-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | curation | CFTR-France | Jan 29, 2018 | when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD - |
CFTR-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 30, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at