rs397508210
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000492.4(CFTR):c.1450C>T(p.His484Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000807 in 1,611,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H484R) has been classified as Uncertain significance.
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.1450C>T | p.His484Tyr | missense_variant | 11/27 | ENST00000003084.11 | |
CFTR-AS1 | NR_149084.1 | n.221+1212G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.1450C>T | p.His484Tyr | missense_variant | 11/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152048Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251326Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135840
GnomAD4 exome AF: 0.00000617 AC: 9AN: 1459252Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 726170
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152048Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74278
ClinVar
Submissions by phenotype
Cystic fibrosis Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 21, 2022 | The p.H484Y variant (also known as c.1450C>T), located in coding exon 11 of the CFTR gene, results from a C to T substitution at nucleotide position 1450. The histidine at codon 484 is replaced by tyrosine, an amino acid with similar properties. This alteration was identified in an individual with congenital absence of the vas deferens (CAVD) (Casals T et al. Hum Reprod, 2000 Jul;15:1476-83). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 16, 2022 | This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 484 of the CFTR protein (p.His484Tyr). This variant is present in population databases (rs397508210, gnomAD 0.009%). This missense change has been observed in individual(s) with congenital absence of vas deferens (CAVD), but a second possibly causative variant was not identified (PMID: 10875853). ClinVar contains an entry for this variant (Variation ID: 53257). 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. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 07, 2018 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 02, 2023 | Variant summary: CFTR c.1450C>T (p.His484Tyr) results in a conservative amino acid change located in the AAA+ ATPase domain (IPR003593) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251326 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1450C>T has been reported in the literature in an individual affected with Congenital Bilateral Absence of the Vas Deferens without an identified second allele (Casals_2000). These reports do not provide unequivocal conclusions about association of the variant with Congenital Bilateral Absence Of The Vas Deferens. 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: 10875853, 18556774, 25735457, 26277102). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Hereditary pancreatitis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center of Genomic medicine, Geneva, University Hospital of Geneva | Apr 27, 2018 | This recessive variant was identified in a patient with repetitive pancreatitis. The patient harbours also a second variant (see below) in this gene in compound heterozygosity - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 08, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at