12-120978841-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1_SupportingPM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.73G>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to proline at codon 25 (p.(Ala25Pro)) of NM_000545.8. This variant is located within the DNA dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting) and is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has a REVEL score of 0.684, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function. This variant was identified in an individual with a MODY Probability Calculator score > 50% and antibody-negative; however, HNF4A was not tested, so PP4 cannot be applied (PMID:15841481). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 15841481, 21224407). In summary, c.73G>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 (specification version 2.1.0, approved 8/11/2023): PM1_Supporting, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA386952675/MONDO:0015967/017

Frequency

Genomes: not found (cov: 32)

Consequence

HNF1A
NM_000545.8 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:1

Conservation

PhyloP100: 2.77

Publications

0 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 links:

HNF1A-AS1 (HGNC:26785): (HNF1A antisense RNA 1)

HNF1A-AS1 links:

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ACMG classification

Classification was made for transcript

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

PM1

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

PM2

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.73G>C	p.Ala25Pro	missense_variant	Exon 1 of 10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2 link	c.73G>C	p.Ala25Pro	missense_variant	Exon 1 of 10		NP_001293108.2
HNF1A	NM_001406915.1 link	c.73G>C	p.Ala25Pro	missense_variant	Exon 1 of 9		NP_001393844.1
HNF1A	XM_024449168.2 link	c.73G>C	p.Ala25Pro	missense_variant	Exon 1 of 9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11 link	c.73G>C	p.Ala25Pro	missense_variant	Exon 1 of 10	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

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.73G>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to proline at codon 25 (p.(Ala25Pro)) of NM_000545.8. This variant is located within the DNA dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting) and is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has a REVEL score of 0.684, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function. This variant was identified in an individual with a MODY Probability Calculator score > 50% and antibody-negative; however, HNF4A was not tested, so PP4 cannot be applied (PMID: 15841481). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 15841481, 21224407). In summary, c.73G>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 (specification version 2.1.0, approved 8/11/2023): PM1_Supporting, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.67

.;D;T;D;T;.

Eigen

Benign

0.082

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.97

D;D;D;D;D;D

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.96

D;D;D;D;D;D

MetaSVM

Uncertain

0.78

PhyloP100

2.8

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.6

N;.;.;.;N;N

REVEL

Pathogenic

0.68

Sift

Benign

0.15

T;.;.;.;T;T

Sift4G

Benign

0.10

T;T;T;T;T;T

Polyphen

0.26

.;.;.;.;.;B

Vest4

0.56

MutPred

0.88

Gain of methylation at K23 (P = 0.103);Gain of methylation at K23 (P = 0.103);Gain of methylation at K23 (P = 0.103);Gain of methylation at K23 (P = 0.103);Gain of methylation at K23 (P = 0.103);Gain of methylation at K23 (P = 0.103);

MVP

0.97

MPC

0.22

ClinPred

0.57

GERP RS

3.4

PromoterAI

0.0099

Neutral

(source)

gMVP

0.83

Mutation Taster

=1/99

disease causing

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over