NM_000545.8:c.1460G>A

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP6_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 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) 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 ACMG Germline Pathogenicity v2019

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: Benign. The variant received -12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 2 star(s). ClinVar submissions strongly and reliably favor benignity (15/15 total B/LB).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.5171 — exceeds 5%% threshold (BA1 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