rs142204928

chr20-44414519-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_175914.5(HNF4A):c.439G>A(p.Val147Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000959 in 1,614,194 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (20 hom.)
• Consequence: HNF4A NM_175914.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11 O:1
• Conservation: PhyloP100: 1.24

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 -11 ACMG points.

• PM1: In a domain NR LBD (size 230) in uniprot entity HNF4A_HUMAN there are 94 pathogenic changes around while only 6 benign (94%) in NM_175914.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0075802803).
• BP6: Variant 20-44414519-G-A is Benign according to our data. Variant chr20-44414519-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36353.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, not_provided=1, Likely_benign=3, Uncertain_significance=1}. Variant chr20-44414519-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000722 (110/152334) while in subpopulation SAS AF= 0.0141 (68/4830). AF 95% confidence interval is 0.0114. There are 0 homozygotes in gnomad4. There are 62 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 110 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF4A	NM_175914.5	c.439G>A	p.Val147Ile	missense_variant	5/10	ENST00000316673.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF4A	ENST00000316673.9	c.439G>A	p.Val147Ile	missense_variant	5/10	1	NM_175914.5

Frequencies

GnomAD3 genomes AF: 0.000723 AC: 110 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00288

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00201 AC: 505 AN: 251390 Hom.: 6 AF XY: 0.00241 AC XY: 327 AN XY: 135866

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00185

Gnomad SAS exome AF: 0.0141

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000202

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000984 AC: 1438 AN: 1461860 Hom.: 20 Cov.: 33 AF XY: 0.00133 AC XY: 968 AN XY: 727226

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00174

Gnomad4 SAS exome AF: 0.0123

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.000186

Gnomad4 OTH exome AF: 0.00141

GnomAD4 genome AF: 0.000722 AC: 110 AN: 152334 Hom.: 0 Cov.: 32 AF XY: 0.000832 AC XY: 62 AN XY: 74502

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00289

Gnomad4 SAS AF: 0.0141

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000341 Hom.: 0

Bravo AF: 0.000366

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00234 AC: 284

Asia WGS AF: 0.0110 AC: 37 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:11 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	HNF4A: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 13, 2020	This variant is associated with the following publications: (PMID: 32621647, 31216263, 25041077, 27080136, 27535533, 27810688, 15281001, 24097065) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	May 02, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 14, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Type 2 diabetes mellitus Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The heterozygous p.Val147Ile variant in HNF4A has been identified in 3 Philippino siblings from 1 family with maturity onset diabetes of the young and 2 individuals without diabetes mellitus (PMID: 15281001, 24097065), but has also been identified in >1% of South Asian chromosomes and 4 homozygotes by ExAC (http://gnomad.broadinstitute.org/). Please note that individuals in ExAC may have type II diabetes. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal dominant diabetes mellitus type 2. -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -

Maturity-onset diabetes of the young type 1 Benign:1 Other:1

not provided, no classification provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 02, 2015	- -
Likely benign, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Familial hyperinsulinism Benign:1

Likely benign, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Maturity onset diabetes mellitus in young Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 27, 2021

This alteration is classified as 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	0.069
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Benign	14
Dann	Benign	0.91
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.79	T;T;T;T;T;T;T
MetaRNN	Benign	0.0076	T;T;T;T;T;T;T
MetaSVM	Benign	-0.46	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.23	N;.;N;.;N;N;N
REVEL	Uncertain	0.54
Sift	Benign	0.49	T;.;T;.;T;T;T
Sift4G	Benign	0.30	T;T;T;T;T;T;T
Polyphen		0.0010, 0.0	.;B;B;.;B;B;.
Vest4		0.15
MVP		0.97
MPC		0.23
ClinPred		0.0069	T
GERP RS		-3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.074
gMVP		0.19

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: rs142204928; hg19: chr20-43043159; COSMIC: COSV105143902;