20-44413724-C-T
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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
NM_175914.5 missense
Scores
1
8
7
Clinical Significance
Conservation
PhyloP100: 7.87
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 GnomAd4 at 3818 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HNF4A | NM_175914.5 | c.350C>T | p.Thr117Ile | missense_variant | 4/10 | ENST00000316673.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HNF4A | ENST00000316673.9 | c.350C>T | p.Thr117Ile | missense_variant | 4/10 | 1 | NM_175914.5 |
Frequencies
GnomAD3 genomes ? AF: 0.0251 AC: 3815AN: 151994Hom.: 72 Cov.: 31
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GnomAD3 exomes AF: 0.0308 AC: 7718AN: 250866Hom.: 150 AF XY: 0.0300 AC XY: 4070AN XY: 135632
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GnomAD4 exome AF: 0.0300 AC: 43792AN: 1461424Hom.: 748 Cov.: 32 AF XY: 0.0298 AC XY: 21648AN XY: 727022
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GnomAD4 genome ? AF: 0.0251 AC: 3818AN: 152112Hom.: 74 Cov.: 31 AF XY: 0.0251 AC XY: 1869AN XY: 74344
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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 submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 28, 2016 | Variant 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 submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 05, 2013 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 23, 2019 | This 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) - |
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. - |
Type 2 diabetes mellitus Benign:1
Benign, criteria provided, single submitter | research | Clinical 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 submitter | research | Personalized Diabetes Medicine Program, University of Maryland School of Medicine | Jan 25, 2019 | ACMG 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 submitter | clinical testing | Ambry Genetics | Jul 16, 2015 | 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. - |
Maturity-onset diabetes of the young type 1 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). 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D;D
MetaRNN
Benign
T;T;T;T;T;T;T
MetaSVM
Uncertain
T
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;.;N;.;N;N;N
REVEL
Uncertain
Sift
Benign
T;.;T;.;T;T;T
Sift4G
Benign
T;T;T;T;T;T;T
Polyphen
0.0090, 0.0040, 0.0010
.;B;B;.;B;B;.
Vest4
MPC
0.68
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at