HNF1A p.Ser487Asn

Variant names:

• chr12-120997624-G-A
• rs2464196
• NM_000545.8:c.1460G>A
• HNF1A p.Ser487Asn

Your query was ambiguous. Multiple possible variants found:

• chr12-120997624-G-A
• chr12-120997624-GC-AT

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-3 Likely Benign

-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). O4_SupportingB1_Strong

The NM_000545.8(HNF1A):c.1460G>A (p.Ser487Asn) 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 allele was found at a cumulative frequency of 0.309 (AC=497,531) in the gnomAD database across 1,612,298 control chromosomes, including 80,461 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.517. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.S487G: Uncertain_significance (ClinVar VariationId 3237446, 1 star) The variant has been observed in cBioPortal in 12 samples across 6 studies and 11 cancer types; somatic enrichment level: SUPPORTING (Observed repeatedly in cBioPortal somatic datasets.). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.27 (6416 hom., cov: 32)
  • Exomes 𝑓: 0.31 (74045 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15 O:1
• 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: Likely_benign. The variant received -3 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O4Enriched in somatic variant database		Enriched in cBioPortal (pre-computed score ≥ 1.0) — Supporting (O4); cBioPortal: samples=12 | studies=6 | cancer types=11 | level=SUPPORTING | points=1.0 | reason: Observed repeatedly in cBioPortal somatic datasets.
	B1High frequency in general population		GnomAD effective popmax AF >1% — B1 stand-alone benign; GnomAD effective popmax AF = 0.517 — exceeds 1% threshold (B1 applied)

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>A p.Ser487Asn	missense	Exon 7 of 10	Prot: NP_000536.6
	HNF1A NM_001306179.2		c.1460G>A p.Ser487Asn	missense	Exon 7 of 10	Prot: NP_001293108.2 UniProt:
	HNF1A NM_001406915.1		c.1309+882G>A	intron	Intron 6 of 8	Prot: NP_001393844.1

HNF1A NM_000545.8

MANE Select

HGVSc / HGVSpc.1460G>Ap.Ser487Asn

Exon rankExon 7 of 10

missense

Prot: NP_000536.6

HNF1A NM_001306179.2

HGVSc / HGVSpc.1460G>Ap.Ser487Asn

Exon rankExon 7 of 10

missense

Prot: NP_001293108.2UniProt: F5H0K0E0YMI7P20823

HNF1A NM_001406915.1

HGVSc / HGVSpc.1309+882G>A

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>A p.Ser487Asn	missense	Exon 7 of 10	Prot: ENSP00000257555.5 UniProt:
	HNF1A ENST00000544413.2	TSL:1	c.1460G>A p.Ser487Asn	missense	Exon 7 of 10	Prot: ENSP00000438804.1 UniProt:
	HNF1A ENST00000538646.5	TSL:1	n.*436G>A	3_prime_UTR	Exon 6 of 6	Prot: ENSP00000443964.1 UniProt:

HNF1A ENST00000257555.11

TSL:1MANE Select

HGVSc / HGVSpc.1460G>Ap.Ser487Asn

Exon rankExon 7 of 10

missense

Prot: ENSP00000257555.5UniProt: P20823-1

HNF1A ENST00000544413.2

TSL:1

HGVSc / HGVSpc.1460G>Ap.Ser487Asn

Exon rankExon 7 of 10

missense

Prot: ENSP00000438804.1UniProt: F5H0K0

HNF1A ENST00000538646.5

TSL:1

HGVSc / HGVSpn.*436G>A

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.273	AC:41508	Hom:6414	AN:152026	Cov:32
GnomAD2 exomes	AF: 0.337	AC:83546	Hom:	AN:247590	Cov:
GnomAD4 exome	AF: 0.312	AC:456021	Hom:74045	AN:1460154	Cov:42
GnomAD4 genome	AF: 0.273	AC:41510	Hom:6416	AN:152144	Cov:32
TOPMed (Bravo)	AF: 0.267	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.299	AC:171231	Hom:27359	AN:571728	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.289	AC:677	Hom:102	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.474	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.303	AC:91	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.247	AC:3217	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.419	AC:1452	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.551	AC:3983	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.531	AC:1047	Hom:	AN:1972	Cov:
Turkish Variome	AF: 0.429	AC:2754	Hom:598	AN:6422	Cov:
UK10K	AF: 0.297	AC:2246	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.485	AC:4347	Hom:1083	AN:8960	Cov:

Showing 16 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.290 *	3214	11066	0.295 *	5095	17260
BipEx(Bipolar disorder (including schizoaffective))	0.300	8524	28420	0.295	8496	28844
Epi25(Epilepsy)	0.305	12791	41958	0.299	20015	66888
SCHEMA(Schizophrenia)	0.357	55621	155870	0.347	87597	252194

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (7)
-	-	3	Maturity-onset diabetes of the young type 3 (3)
-	-	3	not provided (3)
-	-	1	Maturity-onset diabetes of the young (1)
-	-	1	Nonpapillary renal cell carcinoma (1)
-	-	1	Type 2 diabetes mellitus (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	19
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.83	D
GPN-Star LLR	N/A	-3.6
GPN-Star score	N/A	3.6
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
Mutation Taster	N/A	99/1	polymorphism (auto)
PhyloP100	Benign	1.1
popEVE	Benign	-3.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.61	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1
REVEL	Uncertain	0.35
Sift	Benign	0.11	T
Sift4G	Benign	0.27	T
VESM-3B	Benign	-4.3

Showing 26 of 26 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;

COSMIC: COSV57459963;

COSMIC: COSV57459963;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar