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rs1169288

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BA1

The NM_000545.8(HNF1A):c.79A>C(p.Ile27Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,612,800 control chromosomes in the GnomAD database, including 91,048 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I27S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.29 ( 7186 hom., cov: 32)
Exomes 𝑓: 0.33 ( 83862 hom. )

Consequence

HNF1A
NM_000545.8 missense

Scores

5
11

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:13O:3

Conservation

PhyloP100: 3.21
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]
HNF1A-AS1 (HGNC:26785): (HNF1A antisense RNA 1)

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000545.8
BP4
Computational evidence support a benign effect (MetaRNN=0.0011825562).
BP6
Variant 12-120978847-A-C is Benign according to our data. Variant chr12-120978847-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14937.We mark this variant Likely_benign, oryginal submissions are: {Likely_pathogenic=1, Benign=12, not_provided=1}. Variant chr12-120978847-A-C is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.401 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HNF1ANM_000545.8 linkuse as main transcriptc.79A>C p.Ile27Leu missense_variant 1/10 ENST00000257555.11
HNF1ANM_001306179.2 linkuse as main transcriptc.79A>C p.Ile27Leu missense_variant 1/10
HNF1ANM_001406915.1 linkuse as main transcriptc.79A>C p.Ile27Leu missense_variant 1/9
HNF1AXM_024449168.2 linkuse as main transcriptc.79A>C p.Ile27Leu missense_variant 1/9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HNF1AENST00000257555.11 linkuse as main transcriptc.79A>C p.Ile27Leu missense_variant 1/101 NM_000545.8 P4
HNF1A-AS1ENST00000619441.1 linkuse as main transcriptn.128+1797T>G intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.289
AC:
43843
AN:
151834
Hom.:
7184
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.125
Gnomad AMI
AF:
0.400
Gnomad AMR
AF:
0.344
Gnomad ASJ
AF:
0.458
Gnomad EAS
AF:
0.411
Gnomad SAS
AF:
0.417
Gnomad FIN
AF:
0.404
Gnomad MID
AF:
0.522
Gnomad NFE
AF:
0.328
Gnomad OTH
AF:
0.311
GnomAD3 exomes
AF:
0.355
AC:
88280
AN:
248756
Hom.:
16580
AF XY:
0.361
AC XY:
48797
AN XY:
135090
show subpopulations
Gnomad AFR exome
AF:
0.118
Gnomad AMR exome
AF:
0.367
Gnomad ASJ exome
AF:
0.467
Gnomad EAS exome
AF:
0.415
Gnomad SAS exome
AF:
0.427
Gnomad FIN exome
AF:
0.399
Gnomad NFE exome
AF:
0.337
Gnomad OTH exome
AF:
0.361
GnomAD4 exome
AF:
0.333
AC:
487181
AN:
1460848
Hom.:
83862
Cov.:
43
AF XY:
0.338
AC XY:
245420
AN XY:
726756
show subpopulations
Gnomad4 AFR exome
AF:
0.116
Gnomad4 AMR exome
AF:
0.367
Gnomad4 ASJ exome
AF:
0.469
Gnomad4 EAS exome
AF:
0.464
Gnomad4 SAS exome
AF:
0.421
Gnomad4 FIN exome
AF:
0.387
Gnomad4 NFE exome
AF:
0.320
Gnomad4 OTH exome
AF:
0.341
GnomAD4 genome
AF:
0.289
AC:
43847
AN:
151952
Hom.:
7186
Cov.:
32
AF XY:
0.298
AC XY:
22137
AN XY:
74284
show subpopulations
Gnomad4 AFR
AF:
0.125
Gnomad4 AMR
AF:
0.344
Gnomad4 ASJ
AF:
0.458
Gnomad4 EAS
AF:
0.411
Gnomad4 SAS
AF:
0.416
Gnomad4 FIN
AF:
0.404
Gnomad4 NFE
AF:
0.328
Gnomad4 OTH
AF:
0.317
Alfa
AF:
0.327
Hom.:
9956
Bravo
AF:
0.274
TwinsUK
AF:
0.316
AC:
1170
ALSPAC
AF:
0.318
AC:
1226
ESP6500AA
AF:
0.121
AC:
532
ESP6500EA
AF:
0.335
AC:
2881
ExAC
AF:
0.348
AC:
42182
Asia WGS
AF:
0.408
AC:
1414
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Benign:13Other:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Maturity-onset diabetes of the young type 3 Pathogenic:1Benign:4
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. -
Likely pathogenic, criteria provided, single submitterresearchClinical Genomics, Uppaluri K&H Personalized Medicine Clinic-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 rs1169288 with MODY3. This variant is found to be a potent moderate impact variant with a CADD score of 22.4 and sufficient scientific evidence to support the reported classification. Though this is seen to be a tolerated variant as per other insilico scores, this is reported more frequently in MODY cases as per recent evidence. -
Benign, criteria provided, single submitterclinical testingMolecular Genetics, Royal Melbourne HospitalMar 01, 2024- -
Benign, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
not specified Benign:4Other:1
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 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. -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Nov 18, 2014- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
not provided, no classification providedreference populationITMISep 19, 2013- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsJul 12, 2017- -
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Type 2 diabetes mellitus Benign:1
Benign, criteria provided, single submitterresearchClinical Genomics, Uppaluri K&H Personalized Medicine Clinic-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 and response to sulfonylureas.However, evidence shows association of rs1169288 with T2DM and further clinical validation is required in MODY cases. -
Maturity onset diabetes mellitus in young Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsAug 19, 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- -
Insulin resistance, susceptibility to Other:1
risk factor, no assertion criteria providedliterature onlyOMIMJun 01, 2003- -
SERUM HDL CHOLESTEROL LEVEL, MODIFIER OF Other:1
risk factor, no assertion criteria providedliterature onlyOMIMJun 01, 2003- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.24
T
BayesDel_noAF
Uncertain
0.020
Cadd
Benign
21
Dann
Uncertain
0.98
Eigen
Benign
-0.17
Eigen_PC
Benign
-0.019
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.55
T;T;T;T;T;T
MetaRNN
Benign
0.0012
T;T;T;T;T;T
MetaSVM
Benign
-1.2
T
MutationTaster
Benign
0.0043
P;P;P;P;P
PrimateAI
Uncertain
0.67
T
PROVEAN
Benign
-0.92
N;.;.;.;N;N
REVEL
Uncertain
0.47
Sift
Benign
0.082
T;.;.;.;T;T
Sift4G
Benign
0.088
T;T;T;T;T;T
Polyphen
0.020
.;.;.;.;.;B
Vest4
0.24
MPC
0.66
ClinPred
0.020
T
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
gMVP
0.64

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: rs1169288; hg19: chr12-121416650; COSMIC: COSV57459307; API