HNF1A p.Ser487Ile

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr12-120997624-G-T
• chr12-120997624-GC-TA
• chr12-120997624-GC-TT

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 (ACMG Germline Pathogenicity v2019). PM2PP3

The NM_000545.8(HNF1A):c.1460G>T (p.Ser487Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 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: Uncertain_significance. The variant received 3 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — supporting evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Supporting).

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