rs115080759

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000545.8(HNF1A):ā€‹c.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

Genomes: š‘“ 0.0018 ( 1 hom., cov: 32)
Exomes š‘“: 0.00021 ( 3 hom. )

Consequence

HNF1A
NM_000545.8 missense

Scores

6
12

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:9O:1

Conservation

PhyloP100: -0.192
Variant links:
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 Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.01267907).
BP6
Variant 12-120996598-T-G is Benign according to our data. Variant chr12-120996598-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134511.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, not_provided=1, Benign=2, Likely_risk_allele=1}. Variant chr12-120996598-T-G is described in Lovd as [Benign].
BS2
High AC in GnomAd4 at 281 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HNF1ANM_000545.8 linkuse as main transcriptc.1165T>G p.Leu389Val missense_variant 6/10 ENST00000257555.11 NP_000536.6
HNF1ANM_001306179.2 linkuse as main transcriptc.1165T>G p.Leu389Val missense_variant 6/10 NP_001293108.2
HNF1ANM_001406915.1 linkuse as main transcriptc.1165T>G p.Leu389Val missense_variant 6/9 NP_001393844.1
HNF1AXM_024449168.2 linkuse as main transcriptc.1165T>G p.Leu389Val missense_variant 6/9 XP_024304936.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HNF1AENST00000257555.11 linkuse as main transcriptc.1165T>G p.Leu389Val missense_variant 6/101 NM_000545.8 ENSP00000257555 P4

Frequencies

GnomAD3 genomes
AF:
0.00185
AC:
282
AN:
152096
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00647
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000785
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000959
GnomAD3 exomes
AF:
0.000434
AC:
109
AN:
250884
Hom.:
0
AF XY:
0.000287
AC XY:
39
AN XY:
135684
show subpopulations
Gnomad AFR exome
AF:
0.00599
Gnomad AMR exome
AF:
0.000347
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000213
AC:
312
AN:
1461826
Hom.:
3
Cov.:
36
AF XY:
0.000190
AC XY:
138
AN XY:
727216
show subpopulations
Gnomad4 AFR exome
AF:
0.00771
Gnomad4 AMR exome
AF:
0.000268
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.000497
GnomAD4 genome
AF:
0.00185
AC:
281
AN:
152214
Hom.:
1
Cov.:
32
AF XY:
0.00172
AC XY:
128
AN XY:
74416
show subpopulations
Gnomad4 AFR
AF:
0.00643
Gnomad4 AMR
AF:
0.000784
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000949
Alfa
AF:
0.000335
Hom.:
1
Bravo
AF:
0.00183
ESP6500AA
AF:
0.00613
AC:
27
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000544
AC:
66
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Benign:9Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Benign:3Other:1
Likely benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoJan 19, 2021- -
not provided, no classification providedreference populationITMISep 19, 2013- -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsJul 27, 2020- -
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 14, 2021Variant 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 submitterresearchClinical Genomics, Uppaluri K&H Personalized Medicine ClinicFeb 10, 2024Mutations 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 submitterclinical testingMendelicsMay 28, 2019- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 17, 2024- -
Likely benign, criteria provided, single submitterclinical testingGeneDxDec 13, 2017This 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 submitterclinical testingKCCC/NGS Laboratory, Kuwait Cancer Control CenterJul 07, 2023- -
Maturity onset diabetes mellitus in young Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsApr 05, 2021This 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 submitterresearchPersonalized Diabetes Medicine Program, University of Maryland School of MedicineJan 26, 2018ACMG criteria: PP3 (5 predictors), BP4 (4 predictors), BS2 (17 cases and 16 controls in T2DM, 169 hets in gnomAD)=likely benign -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.15
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.59
.;D;T;.
Eigen
Benign
-0.063
Eigen_PC
Benign
-0.094
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Benign
0.80
T;T;T;T
M_CAP
Benign
0.062
D
MetaRNN
Benign
0.013
T;T;T;T
MetaSVM
Uncertain
0.28
D
MutationTaster
Benign
0.90
D;D;D;D;N
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
-1.4
N;.;N;N
REVEL
Uncertain
0.44
Sift
Benign
0.057
T;.;T;T
Sift4G
Benign
0.15
T;T;T;T
Polyphen
0.72
.;.;.;P
Vest4
0.40
MVP
0.89
MPC
0.22
ClinPred
0.023
T
GERP RS
0.77
gMVP
0.63

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs115080759; hg19: chr12-121434401; COSMIC: COSV104568550; COSMIC: COSV104568550; API