12-120993550-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.557T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of isoleucine to threonine at codon 186 (p.(Ile186Thr)) of transcript NM_000545.8. This variant was identified in an individual with a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and antibody negative) (PP4_Moderate; [internal lab contributors]). This variant is located in the HNF1A DNA binding domain, but outside of the region defined as critical for the protein’s function by the ClinGen MDEP (codons 107-174 and 201-280); therefore, PM1_Supporting is not met. The gnomAD PopMax filtering allele frequency of the c.557TC meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.1.0, approved 8/11/23): PP4_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA160013/MONDO:0015967/017

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

HNF1A
NM_000545.8 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:2O:1

Conservation

PhyloP100: 2.41

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

monogenic diabetes
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
type 1 diabetes mellitus 20
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp
diabetes mellitus, noninsulin-dependent
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
maturity-onset diabetes of the young type 3
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
hyperinsulinism due to HNF1A deficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
maturity-onset diabetes of the young
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
nonpapillary renal cell carcinoma
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

HNF1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
HNF1A	NM_000545.8 link	c.557T>C	p.Ile186Thr	missense_variant	Exon 3 of 10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2 link	c.557T>C	p.Ile186Thr	missense_variant	Exon 3 of 10		NP_001293108.2
HNF1A	NM_001406915.1 link	c.557T>C	p.Ile186Thr	missense_variant	Exon 3 of 9		NP_001393844.1
HNF1A	XM_024449168.2 link	c.557T>C	p.Ile186Thr	missense_variant	Exon 3 of 9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11 link	c.557T>C	p.Ile186Thr	missense_variant	Exon 3 of 10	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

GnomAD2 exomes

AF:

0.0000318

AC:

AN:

251348

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000280

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33476

American (AMR)

AF:

0.0000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000297

AC:

AN:

1112002

Other (OTH)

AF:

0.0000166

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152112

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74306

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41412

American (AMR)

AF:

0.0000655

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000676

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Maturity onset diabetes mellitus in young

Uncertain:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

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. However, more evidence is required to confer the association of this particular variant rs587778396 with MODY3. -

Monogenic diabetes

Uncertain:1

Jun 18, 2025

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

The c.557T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of isoleucine to threonine at codon 186 (p.(Ile186Thr)) of transcript NM_000545.8. This variant was identified in an individual with a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and antibody negative) (PP4_Moderate; [internal lab contributors]). This variant is located in the HNF1A DNA binding domain, but outside of the region defined as critical for the protein’s function by the ClinGen MDEP (codons 107-174 and 201-280); therefore, PM1_Supporting is not met. The gnomAD PopMax filtering allele frequency of the c.557T<C variant in gnomAD v2.1.1 is 0.00002294, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant has a REVEL score of 0.326, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on HNF1A function. In summary, c.557T>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.1.0, approved 8/11/23): PP4_Moderate. -

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.063

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.37

DEOGEN2

Benign

0.23

.;T;T;T;T;.

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.75

T;T;T;T;T;T

M_CAP

Pathogenic

0.36

MetaRNN

Benign

0.075

T;T;T;T;T;T

MetaSVM

Pathogenic

1.2

PhyloP100

2.4

PrimateAI

Uncertain

0.66

PROVEAN

Benign

1.1

N;.;.;.;N;N

REVEL

Uncertain

0.33

Sift

Benign

1.0

T;.;.;.;T;T

Sift4G

Benign

0.60

T;T;T;T;T;T

Polyphen

0.0010

.;.;.;.;.;B

Vest4

0.071

MutPred

0.35

Gain of phosphorylation at I186 (P = 0.0157);Gain of phosphorylation at I186 (P = 0.0157);Gain of phosphorylation at I186 (P = 0.0157);Gain of phosphorylation at I186 (P = 0.0157);Gain of phosphorylation at I186 (P = 0.0157);Gain of phosphorylation at I186 (P = 0.0157);

MVP

0.49

MPC

1.2

ClinPred

0.039

GERP RS

2.5

gMVP

0.83

Mutation Taster

=89/11

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over