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GeneBe

rs1800961

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_175914.5(HNF4A):c.350C>T(p.Thr117Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0295 in 1,613,536 control chromosomes in the GnomAD database, including 822 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 74 hom., cov: 31)
Exomes 𝑓: 0.030 ( 748 hom. )

Consequence

HNF4A
NM_175914.5 missense

Scores

1
8
7

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 7.87
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 -18 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_175914.5
BP4
Computational evidence support a benign effect (MetaRNN=0.0070026815).
BP6
Variant 20-44413724-C-T is Benign according to our data. Variant chr20-44413724-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 129240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-44413724-C-T is described in Lovd as [Benign]. Variant chr20-44413724-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0251 (3818/152112) while in subpopulation AMR AF= 0.051 (779/15262). AF 95% confidence interval is 0.0481. There are 74 homozygotes in gnomad4. There are 1869 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High AC in GnomAd at 3815 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HNF4ANM_175914.5 linkuse as main transcriptc.350C>T p.Thr117Ile missense_variant 4/10 ENST00000316673.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HNF4AENST00000316673.9 linkuse as main transcriptc.350C>T p.Thr117Ile missense_variant 4/101 NM_175914.5 P41235-5

Frequencies

GnomAD3 genomes
AF:
0.0251
AC:
3815
AN:
151994
Hom.:
72
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00587
Gnomad AMI
AF:
0.00439
Gnomad AMR
AF:
0.0507
Gnomad ASJ
AF:
0.0251
Gnomad EAS
AF:
0.0134
Gnomad SAS
AF:
0.0284
Gnomad FIN
AF:
0.0416
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0297
Gnomad OTH
AF:
0.0216
GnomAD3 exomes
AF:
0.0308
AC:
7718
AN:
250866
Hom.:
150
AF XY:
0.0300
AC XY:
4070
AN XY:
135632
show subpopulations
Gnomad AFR exome
AF:
0.00530
Gnomad AMR exome
AF:
0.0454
Gnomad ASJ exome
AF:
0.0273
Gnomad EAS exome
AF:
0.0136
Gnomad SAS exome
AF:
0.0263
Gnomad FIN exome
AF:
0.0414
Gnomad NFE exome
AF:
0.0322
Gnomad OTH exome
AF:
0.0313
GnomAD4 exome
AF:
0.0300
AC:
43792
AN:
1461424
Hom.:
748
Cov.:
32
AF XY:
0.0298
AC XY:
21648
AN XY:
727022
show subpopulations
Gnomad4 AFR exome
AF:
0.00496
Gnomad4 AMR exome
AF:
0.0488
Gnomad4 ASJ exome
AF:
0.0253
Gnomad4 EAS exome
AF:
0.0110
Gnomad4 SAS exome
AF:
0.0256
Gnomad4 FIN exome
AF:
0.0420
Gnomad4 NFE exome
AF:
0.0308
Gnomad4 OTH exome
AF:
0.0276
GnomAD4 genome
AF:
0.0251
AC:
3818
AN:
152112
Hom.:
74
Cov.:
31
AF XY:
0.0251
AC XY:
1869
AN XY:
74344
show subpopulations
Gnomad4 AFR
AF:
0.00585
Gnomad4 AMR
AF:
0.0510
Gnomad4 ASJ
AF:
0.0251
Gnomad4 EAS
AF:
0.0128
Gnomad4 SAS
AF:
0.0284
Gnomad4 FIN
AF:
0.0416
Gnomad4 NFE
AF:
0.0297
Gnomad4 OTH
AF:
0.0213
Alfa
AF:
0.0282
Hom.:
193
Bravo
AF:
0.0245
TwinsUK
AF:
0.0283
AC:
105
ALSPAC
AF:
0.0267
AC:
103
ESP6500AA
AF:
0.00613
AC:
27
ESP6500EA
AF:
0.0328
AC:
282
ExAC
AF:
0.0310
AC:
3769
Asia WGS
AF:
0.0270
AC:
92
AN:
3478
EpiCase
AF:
0.0260
EpiControl
AF:
0.0262

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 28, 2016Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 309/13006=2.3% -
Benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoMar 05, 2013- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxApr 23, 2019This variant is associated with the following publications: (PMID: 26981542, 29632382, 12669197, 20878384, 22995991, 15728204, 24503134, 24097065, 20981092, 10983627, 27884173, 27346685, 28008009, 26551672, 26105150, 24448600, 30297969, 25361053, 26503572) -
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
Familial hyperinsulinism Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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. -
Type 2 diabetes mellitus Benign:1
Benign, criteria provided, single submitterresearchClinical Genomics, Uppaluri K&H Personalized Medicine Clinic-rs1800961, a loss-of-function mutation in HNF4A is associated with poor insulin secretion in response to hyperglycemia. These are associated with MODY1. Patients initially respond well to sulfonylureas but eventually become insulin dependent. This variant is also associated with increased risk of T2DM and periodontitis. -
Monogenic diabetes Benign:1
Benign, criteria provided, single submitterresearchPersonalized Diabetes Medicine Program, University of Maryland School of MedicineJan 25, 2019ACMG criteria: BA1 (Overall MAF in gnomAD 3%, 4.1% in European Finnish and 4.6% Latino), BS2 (549 cases and 492 controls in T2DM)= Benign (Note: ClinVar=benign with 2 stars, Chicago and GeneDx call it benign . BP4 not being used because REVEL 0.426, BP6 no longer applied) -
Maturity onset diabetes mellitus in young Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsJul 16, 2015This 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. -
Maturity-onset diabetes of the young type 1 Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.43
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Uncertain
0.0
Cadd
Benign
22
Dann
Uncertain
0.99
Eigen
Benign
0.062
Eigen_PC
Uncertain
0.23
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.93
D;D;D;D;D;D;D
MetaRNN
Benign
0.0070
T;T;T;T;T;T;T
MetaSVM
Uncertain
-0.031
T
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Pathogenic
0.88
D
PROVEAN
Benign
-2.0
N;.;N;.;N;N;N
REVEL
Uncertain
0.43
Sift
Benign
0.25
T;.;T;.;T;T;T
Sift4G
Benign
0.20
T;T;T;T;T;T;T
Polyphen
0.0090, 0.0040, 0.0010
.;B;B;.;B;B;.
Vest4
0.34
MPC
0.68
ClinPred
0.028
T
GERP RS
5.2
Varity_R
0.33
gMVP
0.69

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: rs1800961; hg19: chr20-43042364; COSMIC: COSV57385393; API