rs139016696
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BS2
The NM_000545.8(HNF1A):c.341G>A(p.Arg114His) variant causes a missense change. The variant allele was found at a frequency of 0.0000483 in 1,614,100 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000047 ( 0 hom. )
Consequence
HNF1A
NM_000545.8 missense
NM_000545.8 missense
Scores
1
10
7
Clinical Significance
Conservation
PhyloP100: 3.58
Genes affected
HNF1A (HGNC:11621): (HNF1 homeobox A) The protein encoded by this gene is a transcription factor required for the expression of several liver-specific genes. The encoded protein functions as a homodimer and binds to the inverted palindrome 5'-GTTAATNATTAAC-3'. Defects in this gene are a cause of maturity onset diabetes of the young type 3 (MODY3) and also can result in the appearance of hepatic adenomas. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM1
In a domain POU-specific atypical (size 95) in uniprot entity HNF1A_HUMAN there are 52 pathogenic changes around while only 3 benign (95%) in NM_000545.8
BS2
High AC in GnomAd4 at 9 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HNF1A | NM_000545.8 | c.341G>A | p.Arg114His | missense_variant | Exon 2 of 10 | ENST00000257555.11 | NP_000536.6 | |
HNF1A | NM_001306179.2 | c.341G>A | p.Arg114His | missense_variant | Exon 2 of 10 | NP_001293108.2 | ||
HNF1A | NM_001406915.1 | c.341G>A | p.Arg114His | missense_variant | Exon 2 of 9 | NP_001393844.1 | ||
HNF1A | XM_024449168.2 | c.341G>A | p.Arg114His | missense_variant | Exon 2 of 9 | XP_024304936.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HNF1A | ENST00000257555.11 | c.341G>A | p.Arg114His | missense_variant | Exon 2 of 10 | 1 | NM_000545.8 | ENSP00000257555.5 |
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152226Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251282Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135830
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GnomAD4 exome AF: 0.0000472 AC: 69AN: 1461874Hom.: 0 Cov.: 33 AF XY: 0.0000481 AC XY: 35AN XY: 727236
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GnomAD4 genome AF: 0.0000591 AC: 9AN: 152226Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74356
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:6Benign:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital | Aug 21, 2020 | This variant substitutes the arginine at position 114 with histidine. This is a semi-conserved residue (the alternate residue histidine is observed in several species) and in silico tools have conflicting predictions about the possible impact of this missense change on protein function. This is a rare variant, observed in 14 of 282,682 alleles in the Genome Aggregation Database (v2.1.1). There are conflicting reports in the literature about the clinical significance of this variant. The p.Arg114His variant has been reported as pathogenic in a single individual with MODY (PMID: 23771925). Clinical details and inheritance information were not available. The p.Arg114His variant has also been reported in a cohort of healthy adults (PMID: 24728327, Table S1). Functional studies assessing transcriptional activation and subcellular nuclear localization showed only modest changes for the p.Arg114His variant in comparison to wildtype HNF1A (PMID: 27899486). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 27, 2021 | This sequence change replaces arginine with histidine at codon 114 of the HNF1A protein (p.Arg114His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs139016696, ExAC 0.009%). This missense change has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 23771925, 27899486). ClinVar contains an entry for this variant (Variation ID: 134508). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect HNF1A function (PMID: 27899486). 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 | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
not specified Uncertain:1Benign:1Other:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 16, 2024 | Variant summary: HNF1A c.341G>A (p.Arg114His) results in a non-conservative amino acid change located in the hepatocyte nuclear factor 1, N-terminal domain (IPR006899) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 252644 control chromosomes. The variant allele was found at a frequency of 4.9e-05 in 1615462 control chromosomes. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in HNF1A causing Maturity Onset Diabetes Of The Young 3 phenotype (2.5e-05). c.341G>A has been reported in the literature in individuals affected with diabetes mellitus and suspected of maturity-onset diabetes of the young (MODY) (e.g. Najmi_2017, Pihoker_2013) as well as in unaffected individuals (e.g. Najmi_2017, Bodian_2014). Experimental studies using HeLa cells in vitro showed that this variant results in 83-100% transactivation activity and 81% nuclear localization compared to wildtype (e.g. Najmi_2017, Kickova_2014). The following publications have been ascertained in the context of this evaluation (PMID: 24728327, 38093550, 27899486, 23771925). ClinVar contains an entry for this variant (Variation ID: 134508). Based on the evidence outlined above, the variant was classified as likely benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 04, 2015 | - - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Diabetes mellitus type 1;C0011860:Type 2 diabetes mellitus;C1838100:Maturity-onset diabetes of the young type 3;C1840646:Hepatic adenomas, familial;C2675866:Type 1 diabetes mellitus 20;CN074294:Nonpapillary renal cell carcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 19, 2024 | - - |
Diabetes mellitus type 1;C0011860:Type 2 diabetes mellitus;C1838100:Maturity-onset diabetes of the young type 3;C2675866:Type 1 diabetes mellitus 20 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Oct 26, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
.;D;T;D;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
T;T;T;T;T;T
MetaSVM
Uncertain
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;.;.;N;N
REVEL
Uncertain
Sift
Benign
T;.;.;.;T;T
Sift4G
Benign
T;T;T;T;T;T
Polyphen
0.51
.;.;.;.;.;P
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at