20-22581870-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_021784.5(FOXA2):c.1372C>A(p.Pro458Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000055 in 1,455,282 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 (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )
Consequence
FOXA2
NM_021784.5 missense
NM_021784.5 missense
Scores
11
3
1
Clinical Significance
Conservation
PhyloP100: 8.07
Genes affected
FOXA2 (HGNC:5022): (forkhead box A2) This gene encodes a member of the forkhead class of DNA-binding proteins. These hepatocyte nuclear factors are transcriptional activators for liver-specific genes such as albumin and transthyretin, and they also interact with chromatin. Similar family members in mice have roles in the regulation of metabolism and in the differentiation of the pancreas and liver. This gene has been linked to sporadic cases of maturity-onset diabetes of the young. Transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Oct 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.905
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FOXA2 | NM_021784.5 | c.1372C>A | p.Pro458Thr | missense_variant | 2/2 | ENST00000419308.7 | |
FOXA2 | NM_153675.3 | c.1354C>A | p.Pro452Thr | missense_variant | 3/3 | ||
FOXA2 | XM_047440133.1 | c.1354C>A | p.Pro452Thr | missense_variant | 3/3 | ||
FOXA2 | XM_047440134.1 | c.1264C>A | p.Pro422Thr | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FOXA2 | ENST00000419308.7 | c.1372C>A | p.Pro458Thr | missense_variant | 2/2 | 1 | NM_021784.5 | P4 | |
FOXA2 | ENST00000377115.4 | c.1354C>A | p.Pro452Thr | missense_variant | 3/3 | 1 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.00000801 AC: 2AN: 249644Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135346
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GnomAD4 exome AF: 0.00000550 AC: 8AN: 1455282Hom.: 0 Cov.: 30 AF XY: 0.00000415 AC XY: 3AN XY: 722402
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GnomAD4 genome ? Cov.: 32
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32
ExAC
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 04, 2022 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with FOXA2-related conditions. This variant is present in population databases (rs749322241, gnomAD 0.006%). This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 458 of the FOXA2 protein (p.Pro458Thr). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
REVEL
Pathogenic
Sift4G
Uncertain
D;D
Polyphen
1.0
.;D
Vest4
MutPred
0.46
.;Gain of MoRF binding (P = 0.0206);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at