rs139016696

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM5BS2

The ENST00000257555.11(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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R114C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

HNF1A
ENST00000257555.11 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1O:1

Conservation

PhyloP100: 3.58

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in ENST00000257555.11

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-120988846-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 972770.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_risk_allele=1, Uncertain_significance=2}.

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
HNF1A	NM_000545.8 linkuse as main transcript	c.341G>A	p.Arg114His	missense_variant	2/10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2 linkuse as main transcript	c.341G>A	p.Arg114His	missense_variant	2/10		NP_001293108.2
HNF1A	NM_001406915.1 linkuse as main transcript	c.341G>A	p.Arg114His	missense_variant	2/9		NP_001393844.1
HNF1A	XM_024449168.2 linkuse as main transcript	c.341G>A	p.Arg114His	missense_variant	2/9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11 linkuse as main transcript	c.341G>A	p.Arg114His	missense_variant	2/10	1	NM_000545.8	ENSP00000257555	P4

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251282

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135830

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000289

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:

0.0000616

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000472

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.0000481

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000558

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000111

Hom.:

Bravo

AF:

0.0000642

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

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	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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Uncertain:1Benign:1Other:1

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	- -
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. -

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.044

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

.;D;T;D;T;.

Eigen

Benign

0.074

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.97

D;D;D;D;D;D

M_CAP

Pathogenic

0.54

MetaRNN

Uncertain

0.47

T;T;T;T;T;T

MetaSVM

Uncertain

0.75

MutationTaster

Benign

0.99

D;D;D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.7

N;.;.;.;N;N

REVEL

Uncertain

0.58

Sift

Benign

0.29

T;.;.;.;T;T

Sift4G

Benign

0.27

T;T;T;T;T;T

Polyphen

0.51

.;.;.;.;.;P

Vest4

0.51

MVP

0.90

MPC

1.2

ClinPred

0.087

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.74

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over