chr12-120997624-G-T

Variant names:

• chr12-120997624-G-T
• rs2464196
• NM_000545.8:c.1460G>T
• HNF1A p.Ser487Ile

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+3 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 3 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO6_Supporting

The NM_000545.8(HNF1A):c.1460G>T (p.Ser487Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene HNF1A is a tumor suppressor gene (CancerMine: 13 TSG, 5 oncogene, 2 driver citations). The gene HNF1A is a known oncogene (CancerMine: 13 TSG, 5 oncogene, 2 driver citations). The gene HNF1A is a cancer driver gene (CancerMine: 13 TSG, 5 oncogene, 2 driver citations). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.S487G: Uncertain_significance (ClinVar VariationId 3237446, 1 star); p.S487N: Benign (ClinVar VariationId 129230, 2 stars)

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05
• Publications: 45 publications found

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, STRONG Submitted by: PanelApp Australia, ClinGen
• type 1 diabetes mellitus 20

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine
• 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: Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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)

Classification according to ACGS-UK Somatic Oncogenicity v2025

Specifications for HNF1A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 3 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])
	O6Computational evidence supports deleterious effect		Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer supports an oncogenic/deleterious effect

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000545.8. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	HNF1A NM_000545.8	MANE Select	c.1460G>T p.Ser487Ile	missense	Exon 7 of 10	Prot: NP_000536.6
	HNF1A NM_001306179.2		c.1460G>T p.Ser487Ile	missense	Exon 7 of 10	Prot: NP_001293108.2 UniProt:
	HNF1A NM_001406915.1		c.1309+882G>T	intron	Intron 6 of 8	Prot: NP_001393844.1

HNF1A NM_000545.8

MANE Select

HGVSc / HGVSpc.1460G>Tp.Ser487Ile

Exon rankExon 7 of 10

missense

Prot: NP_000536.6

HNF1A NM_001306179.2

HGVSc / HGVSpc.1460G>Tp.Ser487Ile

Exon rankExon 7 of 10

missense

Prot: NP_001293108.2UniProt: F5H0K0E0YMI7P20823

HNF1A NM_001406915.1

HGVSc / HGVSpc.1309+882G>T

Exon rankIntron 6 of 8

intron

Prot: NP_001393844.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	HNF1A ENST00000257555.11	TSL:1MANE Select	c.1460G>T p.Ser487Ile	missense	Exon 7 of 10	Prot: ENSP00000257555.5 UniProt:
	HNF1A ENST00000544413.2	TSL:1	c.1460G>T p.Ser487Ile	missense	Exon 7 of 10	Prot: ENSP00000438804.1 UniProt:
	HNF1A ENST00000538646.5	TSL:1	n.*436G>T	3_prime_UTR	Exon 6 of 6	Prot: ENSP00000443964.1 UniProt:

HNF1A ENST00000257555.11

TSL:1MANE Select

HGVSc / HGVSpc.1460G>Tp.Ser487Ile

Exon rankExon 7 of 10

missense

Prot: ENSP00000257555.5UniProt: P20823-1

HNF1A ENST00000544413.2

TSL:1

HGVSc / HGVSpc.1460G>Tp.Ser487Ile

Exon rankExon 7 of 10

missense

Prot: ENSP00000438804.1UniProt: F5H0K0

HNF1A ENST00000538646.5

TSL:1

HGVSc / HGVSpn.*436G>T

Exon rankExon 6 of 6

3_prime_UTR

Prot: ENSP00000443964.1UniProt: P20823-4

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:42
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	22
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.90	D
FuncVEP CTI	Benign	0.27
GPN-Star LLR	N/A	-8.5
GPN-Star score	N/A	8.5
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Pathogenic	0.96	D
Mutation Taster	N/A	91/9	polymorphism
PhyloP100	Benign	1.1
popEVE	Benign	-3.4
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.7	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.078	T
VESM-3B	Benign	-6.5

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs2464196;

hg19: chr12-121435427;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar