rs371475225
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM2BP4_Strong
The NM_000492.4(CFTR):c.3672T>A(p.Asn1224Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000632 in 1,613,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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 Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.3672T>A | p.Asn1224Lys | missense_variant | 22/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.3672T>A | p.Asn1224Lys | missense_variant | 22/27 | 1 | NM_000492.4 | P2 | |
ENST00000456270.1 | n.66-11385A>T | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152128Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000196 AC: 49AN: 250038Hom.: 0 AF XY: 0.000237 AC XY: 32AN XY: 135116
GnomAD4 exome AF: 0.0000684 AC: 100AN: 1460928Hom.: 0 Cov.: 31 AF XY: 0.0000881 AC XY: 64AN XY: 726780
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152246Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74420
ClinVar
Submissions by phenotype
Cystic fibrosis Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 18, 2021 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 30, 2022 | This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1224 of the CFTR protein (p.Asn1224Lys). This variant is present in population databases (rs371475225, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with CFTR-related conditions. ClinVar contains an entry for this variant (Variation ID: 495934). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 30, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 06, 2018 | The CFTR c.3672T>A; p.Asn1224Lys variant (rs371475225) has been observed in trans with a common pathogenic CFTR variant (F508del) in an individual exhibiting no clinical signs of cystic fibrosis (Oca 2009). This variant is observed in the general population at an overall frequency of 0.02% (49/244772 alleles) in the Genome Aggregation Database. The asparagine at codon 1224 is weakly conserved and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be tolerated. However, given the lack of clinical and functional data, the significance of this variant cannot be determined with certainty. References: Oca F et al. Amniotic fluid digestive enzyme analysis is useful for identifying CFTR gene mutations of unclear significance. Clin Chem. 2009 Dec;55(12):2214-7. - |
CFTR-related disorder Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | May 24, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 25, 2023 | The CFTR c.3672T>A variant is predicted to result in the amino acid substitution p.Asn1224Lys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.15% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117267779-T-A) Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 06, 2019 | Variant summary: CFTR c.3672T>A (p.Asn1224Lys) results in a non-conservative amino acid change located in the AAA+ ATPase domain (IPR003593) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 244772 control chromosomes, predominantly at a frequency of 0.0015 within the South Asian subpopulation in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (CF) (0.0015 vs. 0.013), allowing no conclusion about variant significance. However, it cannot be excluded that the variant may still represent a rare ethnic specific polymorphism. c.3672T>A has been reported in the literature in a 2 year old symptom-free individual with a pathogenic CFTR variant (F508del) in trans (Oca 2009), however, the clinical outcome of this case remains uncertain as it is unclear whether the variant may contribute to non-classic CF or CBAVD later. This report therefore does not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. 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 uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at