rs397508548
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PM4_Supporting
The NM_000492.4(CFTR):βc.3371_3373delβ(p.Glu1124del) variant causes a inframe deletion, splice region change. The variant allele was found at a frequency of 0.00000553 in 1,446,594 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (β β ).
Frequency
Genomes: not found (cov: 31)
Exomes π: 0.0000055 ( 0 hom. )
Consequence
CFTR
NM_000492.4 inframe_deletion, splice_region
NM_000492.4 inframe_deletion, splice_region
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.95
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM1
?
In a topological_domain Extracellular (size 13) in uniprot entity CFTR_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000492.4
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_000492.4. Strenght limited to Supporting due to length of the change: 1aa.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.3371_3373del | p.Glu1124del | inframe_deletion, splice_region_variant | 21/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.3371_3373del | p.Glu1124del | inframe_deletion, splice_region_variant | 21/27 | 1 | NM_000492.4 | P2 | |
ENST00000456270.1 | n.177+1613_177+1615del | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250910Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135586
GnomAD3 exomes
AF:
AC:
2
AN:
250910
Hom.:
AF XY:
AC XY:
1
AN XY:
135586
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000553 AC: 8AN: 1446594Hom.: 0 AF XY: 0.00000555 AC XY: 4AN XY: 720810
GnomAD4 exome
AF:
AC:
8
AN:
1446594
Hom.:
AF XY:
AC XY:
4
AN XY:
720810
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cystic fibrosis Uncertain:1Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 13, 2021 | The c.3371_3373delAAG variant (also known as p.E1124del) is located in coding exon 21 of the CFTR gene. This variant results from an in-frame AAG deletion at nucleotide positions 3371 to 3373. This results in the in-frame deletion of a glutamic acid at codon 1124. This variant was first reported in a homozygous Pakistani male with congenital absence of the vas deferens, pancreatitis, and normal sweat chloride levels (Conway SP et al. Pediatr. Pulmonol., 2002 Dec;34:491-5). It was also identified in the homozygous state in another Pakistani individual with cystic fibrosis, elevated immunoreactive trypsinogen, and a borderline sweat chloride level (Lim MT et al. Arch. Dis. Child., 2014 Mar;99:197-202). In an individual with idiopathic chronic pancreatitis, this variant was identified with CFTR p.F508del and SPINK1 p.N34S (Masson E et al. PLoS One, 2013 Aug;8:e73522). In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided, no classification provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | - | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 13, 2021 | Variant summary: CFTR c.3371_3373delAAG (p.Glu1124del) results in an in-frame deletion that is predicted to remove 1 amino acid from the encoded protein. The variant allele was found at a frequency of 8e-06 in 250910 control chromosomes (gnomAD). c.3371_3373delAAG has been reported in the literature in a homozygous individual affected with congenital bilateral absence of the vas deferens and chronic pancreatitis (Conway_2002). Furthermore, the variant was detected along with F508del in a compound heterozygous patient affected with idiopathic chronic pancreatitis (Masson_2013). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 20, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at