rs147638455

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 2P and 14B. BS4BP5PP4_ModerateBS3_SupportingBA1

This summary comes from the ClinGen Evidence Repository: The c.1321A>G p.(Ile441Val) variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0005025, which is greater than the MDEP threshold for BA1 (BA1). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and GAD negative) (PP4_Moderate, internal contributors). There is evidence in vitro that this variant has identical transactivation activity to wildtype, indicating that this variant does not impact protein function (BS3_Supporting, PMID:30191603). This variant does not segregate with diabetes in three families (BS4; internal lab contributors, PMIDs: 25905084, 10227563, 33324081). This variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributors). In summary, c.1321A>G p.(Ile441Val) meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0.0, approved 11/16/2022): BA1, PP4_Moderate, BS3_Supporting, BS4, BP5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA213913/MONDO:0015967/085

Frequency

Genomes: 𝑓 0.00064 ( 3 hom., cov: 31)
Exomes 𝑓: 0.00027 ( 5 hom. )

Consequence

HNF4A
NM_175914.5 missense

Scores

8
11

Clinical Significance

Benign reviewed by expert panel U:7B:7

Conservation

PhyloP100: 7.00
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP4
For more information check the summary or visit ClinGen Evidence Repository.
BP5
For more information check the summary or visit ClinGen Evidence Repository.
BS3
For more information check the summary or visit ClinGen Evidence Repository.
BS4
For more information check the summary or visit ClinGen Evidence Repository.
BA1
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.1321A>G p.Ile441Val 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.1321A>G p.Ile441Val missense_variant Exon 10 of 10 1 NM_175914.5 ENSP00000315180.4 P41235-5

Frequencies

GnomAD3 genomes
AF:
0.000639
AC:
97
AN:
151798
Hom.:
3
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.0582
Gnomad AMR
AF:
0.000460
Gnomad ASJ
AF:
0.000865
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000831
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.0127
Gnomad NFE
AF:
0.000324
Gnomad OTH
AF:
0.00191
GnomAD3 exomes
AF:
0.000370
AC:
93
AN:
251452
Hom.:
0
AF XY:
0.000397
AC XY:
54
AN XY:
135914
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000723
Gnomad ASJ exome
AF:
0.000397
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000131
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000484
Gnomad OTH exome
AF:
0.000814
GnomAD4 exome
AF:
0.000268
AC:
392
AN:
1461886
Hom.:
5
Cov.:
32
AF XY:
0.000298
AC XY:
217
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.000329
Gnomad4 AMR exome
AF:
0.000626
Gnomad4 ASJ exome
AF:
0.000727
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000267
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000183
Gnomad4 OTH exome
AF:
0.000695
GnomAD4 genome
AF:
0.000639
AC:
97
AN:
151918
Hom.:
3
Cov.:
31
AF XY:
0.000768
AC XY:
57
AN XY:
74240
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000459
Gnomad4 ASJ
AF:
0.000865
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000832
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000324
Gnomad4 OTH
AF:
0.00189
Alfa
AF:
0.000527
Hom.:
0
Bravo
AF:
0.000831
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000465
AC:
4
ExAC
AF:
0.000329
AC:
40
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.000545
EpiControl
AF:
0.000771

ClinVar

Significance: Benign
Submissions summary: Uncertain:7Benign:7
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Uncertain:3Benign:3
Dec 31, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 441 of the HNF4A protein (p.Ile441Val). This variant is present in population databases (rs147638455, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with maturity onset diabetes of the young (PMID: 10227563, 21105491, 23247789, 26059258, 31595705, 33846082, 34373539, 35256061). This variant is also known as p.Ile454Val, p.Ile463Val. ClinVar contains an entry for this variant (Variation ID: 36345). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HNF4A protein function. 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. -

Dec 13, 2019
Athena Diagnostics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 05, 2021
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23227446, 27884173, 24097065, 25905084, 26059258, 10227563, 21105491, 10768098, 31264968, 31595705) -

Nov 16, 2015
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 21, 2021
AiLife Diagnostics, AiLife Diagnostics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

HNF4A: BS1 -

not specified Benign:2
Mar 30, 2021
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: HNF4A c.1321A>G (p.Ile441Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 251452 control chromosomes, predominantly at a frequency of 0.00072 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 230 fold of the estimated maximal expected allele frequency for a pathogenic variant in HNF4A causing Maturity Onset Diabetes of the Young 1/Neonatal Diabetes Mellitus phenotype (3.1e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.1321A>G has been reported in the literature (example: deSantana_2019, Majidi_2018). These reports however, do not provide unequivocal conclusions about association of the variant with Maturity Onset Diabetes of the Young 1/Neonatal Diabetes Mellitus. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Guo_2019). Five ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=1) or uncertain significance (n=4). Based on the evidence outlined above, the variant was classified as likely benign. -

Nov 04, 2021
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Familial hyperinsulinism Uncertain:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown 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
Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Autosomal dominant polycystic liver disease Uncertain:1
Sep 01, 2021
Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: research

- -

Maturity-onset diabetes of the young type 1 Uncertain:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Maturity onset diabetes mellitus in young Benign:1
May 21, 2024
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Monogenic diabetes Benign:1
May 27, 2023
ClinGen Monogenic Diabetes Variant Curation Expert Panel
Significance: Benign
Review Status: reviewed by expert panel
Collection Method: curation

The c.1321A>G p.(Ile441Val) variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0005025, which is greater than the MDEP threshold for BA1 (BA1). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and GAD negative) (PP4_Moderate, internal contributors). There is evidence in vitro that this variant has identical transactivation activity to wildtype, indicating that this variant does not impact protein function (BS3_Supporting, PMID: 30191603). This variant does not segregate with diabetes in three families (BS4; internal lab contributors, PMIDs: 25905084, 10227563, 33324081). This variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributors). In summary, c.1321A>G p.(Ile441Val) meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0.0, approved 11/16/2022): BA1, PP4_Moderate, BS3_Supporting, BS4, BP5. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.061
BayesDel_addAF
Benign
-0.097
T
BayesDel_noAF
Uncertain
-0.010
CADD
Benign
19
DANN
Uncertain
1.0
DEOGEN2
Benign
0.22
.;.;T;T;.
Eigen
Benign
0.077
Eigen_PC
Benign
0.19
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.86
D;D;D;D;D
M_CAP
Benign
0.040
D
MetaRNN
Benign
0.0094
T;T;T;T;T
MetaSVM
Benign
-0.66
T
MutationAssessor
Uncertain
2.0
.;.;.;M;.
PrimateAI
Uncertain
0.61
T
PROVEAN
Benign
-0.23
N;N;.;N;N
REVEL
Uncertain
0.35
Sift
Uncertain
0.018
D;D;.;D;D
Sift4G
Benign
0.11
T;T;T;T;T
Polyphen
0.23, 0.14
.;B;.;B;.
Vest4
0.54
MVP
0.94
MPC
0.29
ClinPred
0.083
T
GERP RS
5.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.094
gMVP
0.22

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: rs147638455; hg19: chr20-43058267; API