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GeneBe

rs2464196

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000545.8(HNF1A):c.1460G>A(p.Ser487Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 1,612,298 control chromosomes in the GnomAD database, including 80,461 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.27 ( 6416 hom., cov: 32)
Exomes 𝑓: 0.31 ( 74045 hom. )

Consequence

HNF1A
NM_000545.8 missense

Scores

4
12

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13O:1

Conservation

PhyloP100: 1.05
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 -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.001606971).
BP6
Variant 12-120997624-G-A is Benign according to our data. Variant chr12-120997624-G-A is described in ClinVar as [Benign]. Clinvar id is 129230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-120997624-G-A is described in Lovd as [Benign]. Variant chr12-120997624-G-A is described in Lovd as [Pathogenic].
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.471 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HNF1ANM_000545.8 linkuse as main transcriptc.1460G>A p.Ser487Asn missense_variant 7/10 ENST00000257555.11
HNF1ANM_001306179.2 linkuse as main transcriptc.1460G>A p.Ser487Asn missense_variant 7/10
HNF1AXM_024449168.2 linkuse as main transcriptc.1460G>A p.Ser487Asn missense_variant 7/9
HNF1ANM_001406915.1 linkuse as main transcriptc.1309+882G>A intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HNF1AENST00000257555.11 linkuse as main transcriptc.1460G>A p.Ser487Asn missense_variant 7/101 NM_000545.8 P4

Frequencies

GnomAD3 genomes
AF:
0.273
AC:
41508
AN:
152026
Hom.:
6414
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.128
Gnomad AMI
AF:
0.357
Gnomad AMR
AF:
0.345
Gnomad ASJ
AF:
0.459
Gnomad EAS
AF:
0.487
Gnomad SAS
AF:
0.404
Gnomad FIN
AF:
0.321
Gnomad MID
AF:
0.516
Gnomad NFE
AF:
0.299
Gnomad OTH
AF:
0.305
GnomAD3 exomes
AF:
0.337
AC:
83546
AN:
247590
Hom.:
14870
AF XY:
0.343
AC XY:
45944
AN XY:
134104
show subpopulations
Gnomad AFR exome
AF:
0.119
Gnomad AMR exome
AF:
0.371
Gnomad ASJ exome
AF:
0.462
Gnomad EAS exome
AF:
0.486
Gnomad SAS exome
AF:
0.417
Gnomad FIN exome
AF:
0.312
Gnomad NFE exome
AF:
0.306
Gnomad OTH exome
AF:
0.338
GnomAD4 exome
AF:
0.312
AC:
456021
AN:
1460154
Hom.:
74045
Cov.:
42
AF XY:
0.316
AC XY:
229707
AN XY:
726350
show subpopulations
Gnomad4 AFR exome
AF:
0.121
Gnomad4 AMR exome
AF:
0.373
Gnomad4 ASJ exome
AF:
0.469
Gnomad4 EAS exome
AF:
0.523
Gnomad4 SAS exome
AF:
0.411
Gnomad4 FIN exome
AF:
0.309
Gnomad4 NFE exome
AF:
0.295
Gnomad4 OTH exome
AF:
0.326
GnomAD4 genome
AF:
0.273
AC:
41510
AN:
152144
Hom.:
6416
Cov.:
32
AF XY:
0.280
AC XY:
20838
AN XY:
74374
show subpopulations
Gnomad4 AFR
AF:
0.128
Gnomad4 AMR
AF:
0.345
Gnomad4 ASJ
AF:
0.459
Gnomad4 EAS
AF:
0.486
Gnomad4 SAS
AF:
0.403
Gnomad4 FIN
AF:
0.321
Gnomad4 NFE
AF:
0.299
Gnomad4 OTH
AF:
0.312
Alfa
AF:
0.311
Hom.:
19018
Bravo
AF:
0.267
TwinsUK
AF:
0.294
AC:
1090
ALSPAC
AF:
0.300
AC:
1156
ESP6500AA
AF:
0.123
AC:
541
ESP6500EA
AF:
0.311
AC:
2676
ExAC
AF:
0.331
AC:
40202
Asia WGS
AF:
0.419
AC:
1452
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:13Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:6Other:1
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Likely benign, no assertion criteria providedclinical testingGenetic Services Laboratory, University of Chicago-Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Nov 18, 2014- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
not provided, no classification providedreference populationITMISep 19, 2013- -
Benign, criteria provided, single submitterclinical testingGeneDxAug 21, 2013This 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. -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsJul 12, 2017- -
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Maturity-onset diabetes of the young type 3 Benign:2
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabAug 10, 2021- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMar 06, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Type 2 diabetes mellitus Benign:1
Benign, criteria provided, single submitterresearchClinical Genomics, Uppaluri K&H Personalized Medicine Clinic-rs2464196 of HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria and may respond to sulfonylureas. -
Maturity onset diabetes mellitus in young Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsSep 27, 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. -
Nonpapillary renal cell carcinoma Benign:1
Benign, criteria provided, single submitterclinical testingKCCC/NGS Laboratory, Kuwait Cancer Control CenterJul 07, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.40
T
BayesDel_noAF
Benign
-0.21
Cadd
Benign
19
Dann
Uncertain
0.99
Eigen
Benign
-0.22
Eigen_PC
Benign
-0.10
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Benign
0.52
T;T;T;T;T;T
MetaRNN
Benign
0.0016
T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationTaster
Benign
0.063
P;P;P;P
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-0.61
N;.;.;.;N;N
REVEL
Uncertain
0.35
Sift
Benign
0.11
T;.;.;.;T;T
Sift4G
Benign
0.27
T;T;T;T;T;T
Polyphen
0.0
.;.;.;.;.;B
Vest4
0.13
MPC
0.12
ClinPred
0.0043
T
GERP RS
3.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
gMVP
0.75

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: rs2464196; hg19: chr12-121435427; COSMIC: COSV57459963; COSMIC: COSV57459963; API