rs115080759
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_000545.8(HNF1A):āc.1165T>Gā(p.Leu389Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000367 in 1,614,040 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000545.8 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HNF1A | NM_000545.8 | c.1165T>G | p.Leu389Val | missense_variant | 6/10 | ENST00000257555.11 | NP_000536.6 | |
HNF1A | NM_001306179.2 | c.1165T>G | p.Leu389Val | missense_variant | 6/10 | NP_001293108.2 | ||
HNF1A | NM_001406915.1 | c.1165T>G | p.Leu389Val | missense_variant | 6/9 | NP_001393844.1 | ||
HNF1A | XM_024449168.2 | c.1165T>G | p.Leu389Val | missense_variant | 6/9 | XP_024304936.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HNF1A | ENST00000257555.11 | c.1165T>G | p.Leu389Val | missense_variant | 6/10 | 1 | NM_000545.8 | ENSP00000257555 | P4 |
Frequencies
GnomAD3 genomes AF: 0.00185 AC: 282AN: 152096Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000434 AC: 109AN: 250884Hom.: 0 AF XY: 0.000287 AC XY: 39AN XY: 135684
GnomAD4 exome AF: 0.000213 AC: 312AN: 1461826Hom.: 3 Cov.: 36 AF XY: 0.000190 AC XY: 138AN XY: 727216
GnomAD4 genome AF: 0.00185 AC: 281AN: 152214Hom.: 1 Cov.: 32 AF XY: 0.00172 AC XY: 128AN XY: 74416
ClinVar
Submissions by phenotype
not specified Benign:3Other:1
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 19, 2021 | - - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 27, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 14, 2021 | Variant summary: HNF1A c.1165T>G (p.Leu389Val) results in a conservative amino acid change located in the Hepatocyte nuclear factor 1, beta isoform, C-terminal domain (IPR006897) 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 0.00061 in 284186 control chromosomes, predominantly at a frequency of 0.0063 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 252 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), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1165T>G has been reported in the literature in individuals affected with Maturity Onset Diabetes Of The Young 3 (Bellanne_Chantelot_2008, Jeannot_2010, Flannick_2013) as well as in healthy controls (Bodian_2014). These reports do not provide unequivocal conclusions about association of the variant with Maturity Onset Diabetes Of The Young 3. Two functional studies reported this variant results in reduced transcriptional activity in cells (Najmi_2016, Juszczak_2018). Four ClinVar submitters (evaluation after 2014) cite the variant as benign (n=1) and likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign. - |
Maturity-onset diabetes of the young type 3 Pathogenic:1Benign:1
Likely risk allele, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | Feb 10, 2024 | Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. Sufficient evidence is found to confer the association of this particular variant rs115080759 with MODY3.This variant is a potent moderate impact variant with a CADD score of 20.7 and sufficient scientific evidence to support the reported classification. This is found more frequently in MODY cases as per recent evidence as well. - |
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 17, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 13, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Nonpapillary renal cell carcinoma Benign:1
Likely benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Maturity onset diabetes mellitus in young Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 05, 2021 | 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. - |
Monogenic diabetes Benign:1
Likely benign, criteria provided, single submitter | research | Personalized Diabetes Medicine Program, University of Maryland School of Medicine | Jan 26, 2018 | ACMG criteria: PP3 (5 predictors), BP4 (4 predictors), BS2 (17 cases and 16 controls in T2DM, 169 hets in gnomAD)=likely benign - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at