12-120997588-C-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_000545.8(HNF1A):c.1424C>T(p.Pro475Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000477 in 1,613,720 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P475P) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000050 ( 0 hom. )
Consequence
HNF1A
NM_000545.8 missense
NM_000545.8 missense
Scores
4
11
2
Clinical Significance
Conservation
PhyloP100: 3.83
Genes affected
HNF1A (HGNC:11621): (HNF1 homeobox A) The protein encoded by this gene is a transcription factor required for the expression of several liver-specific genes. The encoded protein functions as a homodimer and binds to the inverted palindrome 5'-GTTAATNATTAAC-3'. Defects in this gene are a cause of maturity onset diabetes of the young type 3 (MODY3) and also can result in the appearance of hepatic adenomas. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
BS2
?
High AC in GnomAdExome at 13 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HNF1A | NM_000545.8 | c.1424C>T | p.Pro475Leu | missense_variant | 7/10 | ENST00000257555.11 | |
HNF1A | NM_001306179.2 | c.1424C>T | p.Pro475Leu | missense_variant | 7/10 | ||
HNF1A | XM_024449168.2 | c.1424C>T | p.Pro475Leu | missense_variant | 7/9 | ||
HNF1A | NM_001406915.1 | c.1309+846C>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HNF1A | ENST00000257555.11 | c.1424C>T | p.Pro475Leu | missense_variant | 7/10 | 1 | NM_000545.8 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152222Hom.: 0 Cov.: 33
GnomAD3 genomes
?
AF:
AC:
4
AN:
152222
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000520 AC: 13AN: 249896Hom.: 0 AF XY: 0.0000591 AC XY: 8AN XY: 135316
GnomAD3 exomes
AF:
AC:
13
AN:
249896
Hom.:
AF XY:
AC XY:
8
AN XY:
135316
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: 0.0000499 AC: 73AN: 1461498Hom.: 0 Cov.: 38 AF XY: 0.0000440 AC XY: 32AN XY: 727078
GnomAD4 exome
AF:
AC:
73
AN:
1461498
Hom.:
Cov.:
38
AF XY:
AC XY:
32
AN XY:
727078
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 ? AF: 0.0000263 AC: 4AN: 152222Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74370
GnomAD4 genome
?
AF:
AC:
4
AN:
152222
Hom.:
Cov.:
33
AF XY:
AC XY:
3
AN XY:
74370
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
1
ExAC
?
AF:
AC:
4
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 11, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Mar 09, 2022 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 26, 2023 | Variant summary: HNF1A c.1424C>T (p.Pro475Leu) results in a non-conservative amino acid change located in the C-terminal domain (IPR006897) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 250026 control chromosomes (gnomAD). The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in HNF1A causing Maturity Onset Diabetes Of The Young 3 phenotype (2.5e-05), suggesting that the variant may be benign. c.1424C>T has been reported in the literature in several individuals affected with diabetes (e.g., Plengvidhya_2009, Billings_2022), however without strong evidence for causality (e.g., lack of co-segregation data) in all cases. The variant was also identified in several unaffected control individuals (e.g., Billings_2022). These reports therefore do not provide unequivocal conclusions about association of the variant with Maturity Onset Diabetes Of The Young 3. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in moderate defects in BCL2L1 transactivation (approx. 28% reduction relative to wildtype) as well as defects in regulation of cell cycle transitions (e.g., Sujjitjoon_2020). The following publications have been ascertained in the context of this evaluation (PMID: 36208030, 18811724, 32684311). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments: three submitters classified the variant as VUS, and one submitter classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Maturity onset diabetes mellitus in young Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 20, 2021 | The p.P475L variant (also known as c.1424C>T), located in coding exon 7 of the HNF1A gene, results from a C to T substitution at nucleotide position 1424. The proline at codon 475 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in a Thai subject with type 2 diabetes (Plengvidhya N et al. Clin Endocrinol (Oxf), 2009 Jun;70:847-53). This variant has been noted to have reduced transactivation activity and affected cell cycle and growth (Sujjitjoon J et al. Biochem Biophys Res Commun, 2020 Aug;529:826-833). This amino acid position is well 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. - |
Monogenic diabetes Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 22, 2020 | The p.Pro475Leu variant in HNF1A has been reported in at least 2 individuals (including 1 Thai individual) with Monogenic Diabetes (PMID: 18811724, 23348805), and has been identified in 0.09954% (10/10046) of Ashkenazi Jewish chromosomes and 0.002659% (3/112840) European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs193922580). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic in ClinVar and as a VUS in the literature (Variation ID: 36801; PMID: 27080136). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Pro475Leu variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3, PS4_Supporting (Richards 2015). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;.;.;D;D
REVEL
Pathogenic
Sift
Uncertain
D;.;.;.;D;D
Sift4G
Uncertain
D;D;D;D;D;D
Polyphen
1.0
.;.;.;.;.;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
gMVP
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