rs202105574

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BS2_Supporting

The NM_175914.5(HNF4A):​c.658G>A​(p.Val220Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,612,620 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain risk allele (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

HNF4A
NM_175914.5 missense

Scores

5
5
9

Clinical Significance

Uncertain significance/Uncertain risk allele criteria provided, multiple submitters, no conflicts P:1U:1O:1

Conservation

PhyloP100: 2.05
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.

PM1
In a domain NR LBD (size 230) in uniprot entity HNF4A_HUMAN there are 50 pathogenic changes around while only 3 benign (94%) in NM_175914.5
BS2
High AC in GnomAd4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HNF4ANM_175914.5 linkc.658G>A p.Val220Met missense_variant Exon 6 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.658G>A p.Val220Met missense_variant Exon 6 of 10 1 NM_175914.5 ENSP00000315180.4 P41235-5

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152194
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000800
AC:
2
AN:
249892
Hom.:
0
AF XY:
0.00000740
AC XY:
1
AN XY:
135192
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000959
AC:
14
AN:
1460308
Hom.:
0
Cov.:
31
AF XY:
0.0000110
AC XY:
8
AN XY:
726536
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000720
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152312
Hom.:
0
Cov.:
31
AF XY:
0.0000403
AC XY:
3
AN XY:
74472
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000135
Hom.:
0
Bravo
AF:
0.000125
ExAC
AF:
0.00000824
AC:
1
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Uncertain significance/Uncertain risk allele
Submissions summary: Pathogenic:1Uncertain:1Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:1Uncertain:1
Jan 29, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 220 of the HNF4A protein (p.Val220Met). This variant is present in population databases (rs202105574, gnomAD 0.005%). This missense change has been observed in individual(s) with HNF4A-related conditions (PMID: 26552609, 30586318, 31291970). This variant is also known as c.724G>A (p.Val242Met). ClinVar contains an entry for this variant (Variation ID: 562363). 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. -

Sep 16, 2018
Gharavi Laboratory, Columbia University
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Maturity onset diabetes mellitus in young Other:1
-
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic
Significance: Uncertain risk allele
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 rs202105574 in MODY, yet. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Pathogenic
0.15
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.30
.;.;.;T;.;D;.
Eigen
Benign
0.14
Eigen_PC
Benign
0.19
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Uncertain
0.94
D;D;D;D;D;D;D
M_CAP
Pathogenic
0.59
D
MetaRNN
Uncertain
0.65
D;D;D;D;D;D;D
MetaSVM
Uncertain
0.50
D
MutationAssessor
Benign
1.5
.;.;.;.;L;L;L
PrimateAI
Pathogenic
0.80
T
PROVEAN
Benign
-1.5
N;.;N;.;N;N;N
REVEL
Pathogenic
0.76
Sift
Benign
0.15
T;.;T;.;T;T;T
Sift4G
Benign
0.22
T;T;T;T;T;T;T
Polyphen
0.88, 0.91, 0.95, 0.73
.;P;P;.;P;P;.
Vest4
0.73
MVP
0.95
MPC
0.85
ClinPred
0.82
D
GERP RS
4.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.28
gMVP
0.48

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: rs202105574; hg19: chr20-43047140; COSMIC: COSV57380521; API