rs147638455

Positions:

• chr20-44429627-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 2P and 14B. BS4 BP5 PP4_Moderate BS3_Supporting BA1

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
• Clinical Significance: Benign reviewed by expert panel U:7 B:7
• Conservation: PhyloP100: 7.00

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF4A	NM_175914.5	c.1321A>G	p.Ile441Val	missense_variant	10/10	ENST00000316673.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF4A	ENST00000316673.9	c.1321A>G	p.Ile441Val	missense_variant	10/10	1	NM_175914.5

Frequencies

GnomAD3 genomes AF: 0.000639 AC: 97 AN: 151798 Hom.: 3 Cov.: 31

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

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

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

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:7 Benign:7

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:3 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 16, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 20, 2023	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). Advanced 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 at Invitae 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Feb 21, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	HNF4A: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 13, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	This variant is associated with the following publications: (PMID: 23227446, 27884173, 24097065, 25905084, 26059258, 10227563, 21105491, 10768098, 31264968, 31595705) -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 30, 2021	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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 04, 2021	- -

Familial hyperinsulinism Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Autosomal dominant polycystic liver disease Uncertain:1

Uncertain significance, no assertion criteria provided

research

Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center

Sep 01, 2021

- -

Maturity-onset diabetes of the young type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

Monogenic diabetes Benign:1

Benign, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

May 27, 2023

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. -

Maturity onset diabetes mellitus in young Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 21, 2024

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. -

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;.
MutationTaster	Benign	1.0	D;D;D;D
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

Other links and lift over

dbSNP: rs147638455; hg19: chr20-43058267;