NM_175914.5:c.454G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.454G>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of glycine to serine at codon 152 (p.(Gly152Ser)) of NM_175914.5. This variant has a gnomAD v2.1.1 Grpmax filtering allele frequency of 0.00000292 (below the MDEP threshold of 0.000003) and <=2 copies observed in the European non-Finnish population and <=1 copies in any other subpopulation, thereby meeting the ClinGen MDEP criteria for PM2_Supporting (PM2_Supporting). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to age of diagnosis over 35 (internal lab contributor). Additionally, this variant has a REVEL score of 0.232, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. In summary, c.454G>A 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 2.0.0, approved 10/11/2023): PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA9870282/MONDO:0015967/085

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

HNF4A
NM_175914.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:2O:1

Conservation

PhyloP100: 6.95

Publications

3 publications found

Variant links:

Genes affected

HNF4A (HGNC:5024): (hepatocyte nuclear factor 4 alpha) The protein encoded by this gene is a nuclear transcription factor which binds DNA as a homodimer. The encoded protein controls the expression of several genes, including hepatocyte nuclear factor 1 alpha, a transcription factor which regulates the expression of several hepatic genes. This gene may play a role in development of the liver, kidney, and intestines. Mutations in this gene have been associated with monogenic autosomal dominant non-insulin-dependent diabetes mellitus type I. Alternative splicing of this gene results in multiple transcript variants encoding several different isoforms. [provided by RefSeq, Apr 2012]

HNF4A Gene-Disease associations (from GenCC):

maturity-onset diabetes of the young type 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
monogenic diabetes
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
diabetes mellitus, noninsulin-dependent
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, G2P
hyperinsulinism due to HNF4A deficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
maturity-onset diabetes of the young
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

HNF4A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF4A	NM_175914.5 link	c.454G>A	p.Gly152Ser	missense_variant	Exon 5 of 10	ENST00000316673.9	NP_787110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF4A	ENST00000316673.9 link	c.454G>A	p.Gly152Ser	missense_variant	Exon 5 of 10	1	NM_175914.5	ENSP00000315180.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000795

AC:

AN:

251446

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000198

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000165

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Monogenic diabetes

Uncertain:2

Aug 18, 2017

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

ACMG Criteria:PP3 (5 predictors), BP4 (6 predictors) -

May 09, 2024

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

The c.454G>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of glycine to serine at codon 152 (p.(Gly152Ser)) of NM_175914.5. This variant has a gnomAD v2.1.1 Grpmax filtering allele frequency of 0.00000292 (below the MDEP threshold of 0.000003) and <=2 copies observed in the European non-Finnish population and <=1 copies in any other subpopulation, thereby meeting the ClinGen MDEP criteria for PM2_Supporting (PM2_Supporting). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to age of diagnosis over 35 (internal lab contributor). Additionally, this variant has a REVEL score of 0.232, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. In summary, c.454G>A 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 2.0.0, approved 10/11/2023): PM2_Supporting. -

Maturity onset diabetes mellitus in young

Other:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Uncertain risk allele

Review Status:criteria provided, single submitter

Collection Method:research

Potent mutations in HNF4A are associated with poor insulin secretion in response to hyperglycemia. Associated with MODY1. Patients initially respond well to sulfonylureas but eventually become insulin dependent. However, more evidence is required to ascertain the role of this particular variant rs760038979 in MODY, yet. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Uncertain

0.032

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.23

.;.;.;T;.;T;.

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.51

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.90

D;D;D;D;D;D;D

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.31

T;T;T;T;T;T;T

MetaSVM

Benign

-0.43

MutationAssessor

Benign

2.0

.;.;.;.;M;M;M

PhyloP100

7.0

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.55

N;.;N;.;N;N;N

REVEL

Benign

0.23

Sift

Benign

0.28

T;.;T;.;T;T;T

Sift4G

Benign

0.85

T;T;T;T;T;T;T

Polyphen

0.0010, 0.023, 0.042, 0.017

.;B;B;.;B;B;.

Vest4

0.55

MutPred

0.35

.;.;.;.;Gain of methylation at K179 (P = 0.0492);Gain of methylation at K179 (P = 0.0492);Gain of methylation at K179 (P = 0.0492);

MVP

0.85

MPC

0.30

ClinPred

0.34

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.76

Mutation Taster

=67/33

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over