rs1063239

Variant summary

Our verdict is Uncertain significance. Variant got -1 ACMG points: 0P and 1B. BP4

This summary comes from the ClinGen Evidence Repository: The c.1267C>T variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of proline to serine at codon 423 (p.(Pro423Ser)) of NM_175914.5. This variant has a gnomAD v2.1.1 Grpmax filtering allele frequency of 0.000002920 (below the MDEP threshold of 0.000003), however, it has > 2 copies observed in the European non-Finnish population and other subpopulations; therefore, this variant does not meet the ClinGen MDEP-established cutoff for PM2_Supporting. This variant is predicted to be benign by computational evidence, with a REVEL score of 0.059, which is less than or equal to the MDEP threshold of 0.15 (BP4). While studies exploring the effect of this variant on protein function have been performed, these studies do not meet the criteria set forth by the MDEP for the application of PS3 or BS3 (PMID:22308320). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50% (PMID:15111529 ). In summary, c.1267C>T meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 10/11/2023): BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA231163/MONDO:0015967/085

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

HNF4A
NM_175914.5 missense

Scores

2
17

Clinical Significance

Uncertain significance reviewed by expert panel U:6

Conservation

PhyloP100: 5.83
Variant links:
Genes affected
HNF4A (HGNC:5024): (hepatocyte nuclear factor 4 alpha) The protein encoded by this gene is a nuclear transcription factor which binds DNA as a homodimer. The encoded protein controls the expression of several genes, including hepatocyte nuclear factor 1 alpha, a transcription factor which regulates the expression of several hepatic genes. This gene may play a role in development of the liver, kidney, and intestines. Mutations in this gene have been associated with monogenic autosomal dominant non-insulin-dependent diabetes mellitus type I. Alternative splicing of this gene results in multiple transcript variants encoding several different isoforms. [provided by RefSeq, Apr 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got -1 ACMG points.

BP4
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HNF4ANM_175914.5 linkc.1267C>T p.Pro423Ser missense_variant Exon 10 of 10 ENST00000316673.9 NP_787110.2 P41235-5F1D8T0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HNF4AENST00000316673.9 linkc.1267C>T p.Pro423Ser missense_variant Exon 10 of 10 1 NM_175914.5 ENSP00000315180.4 P41235-5

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152064
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251382
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135872
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.000298
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000404
AC:
59
AN:
1461864
Hom.:
0
Cov.:
32
AF XY:
0.0000426
AC XY:
31
AN XY:
727232
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.000421
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000369
Gnomad4 OTH exome
AF:
0.0000993
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152064
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74266
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000688
Hom.:
0
Bravo
AF:
0.0000264
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.000164
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Uncertain:2
Jul 23, 2013
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 24, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 423 of the HNF4A protein (p.Pro423Ser). This variant is present in population databases (rs1063239, gnomAD 0.02%). This missense change has been observed in individual(s) with HNF4A-related conditions (PMID: 15111529). This variant is also known as Pro436Ser or Pro445Ser . ClinVar contains an entry for this variant (Variation ID: 129237). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects HNF4A function (PMID: 22308320). 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 specified Uncertain:1
Jul 02, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: HNF4A c.1267C>T (p.Pro423Ser) results in a non-conservative amino acid change in 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 2.4e-05 in 251382 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1267C>T has been reported in the literature in individuals affected with Diabetes (example, Aguilera_2004) and as "not possibly/putatively pathogenic" at-least one case in the Jackson Heart Study cohort, in which a majority (>80%) of variant carriers did not develop diabetes. These report(s) do not provide unequivocal conclusions about association of the variant with Maturity Onset Diabetes Of The Young 1/Neonatal Diabetes Mellitus. To our knowledge, no informative experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15111529, 22308320, 24097065, 30648609). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Type 2 diabetes mellitus;C1852093:Maturity-onset diabetes of the young type 1;C4014962:Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young Uncertain:1
Sep 14, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Monogenic diabetes Uncertain:1
Dec 12, 2024
ClinGen Monogenic Diabetes Variant Curation Expert Panel
Significance: Uncertain significance
Review Status: reviewed by expert panel
Collection Method: curation

The c.1267C>T variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of proline to serine at codon 423 (p.(Pro423Ser)) of NM_175914.5. This variant has a gnomAD v2.1.1 Grpmax filtering allele frequency of 0.000002920 (below the MDEP threshold of 0.000003), however, it has > 2 copies observed in the European non-Finnish population and other subpopulations; therefore, this variant does not meet the ClinGen MDEP-established cutoff for PM2_Supporting. This variant is predicted to be benign by computational evidence, with a REVEL score of 0.059, which is less than or equal to the MDEP threshold of 0.15 (BP4). While studies exploring the effect of this variant on protein function have been performed, these studies do not meet the criteria set forth by the MDEP for the application of PS3 or BS3 (PMID: 22308320). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50% (PMID: 15111529 ). In summary, c.1267C>T meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 10/11/2023): BP4. -

Maturity onset diabetes mellitus in young Uncertain:1
-
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: research

Potent mutations in HNF4A are associated with poor insulin secretion in response to hyperglycemia. Associated with MODY1. Patients initially respond well to sulfonylureas but eventually become insulin dependent. However, more evidence is required to ascertain the role of this particular variant rs1063239 in MODY, yet. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.070
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
19
DANN
Benign
0.87
DEOGEN2
Benign
0.23
.;.;T;T;.
Eigen
Benign
-0.28
Eigen_PC
Benign
-0.10
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.79
T;T;T;T;T
M_CAP
Benign
0.050
D
MetaRNN
Benign
0.080
T;T;T;T;T
MetaSVM
Benign
-0.84
T
MutationAssessor
Benign
0.55
.;.;.;N;.
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-0.10
N;N;.;N;N
REVEL
Benign
0.059
Sift
Benign
0.33
T;T;.;T;T
Sift4G
Benign
0.77
T;T;T;T;T
Polyphen
0.082, 0.0
.;B;.;B;.
Vest4
0.16
MVP
0.56
MPC
0.29
ClinPred
0.063
T
GERP RS
4.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.049
gMVP
0.16

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1063239; hg19: chr20-43058213; API