chr20-44419790-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3PP1_ModeratePP4_ModeratePM2_SupportingPS4

This summary comes from the ClinGen Evidence Repository: The c.740T>C variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of leucine to proline at codon 247 (p.(Leu247Pro)) of NM_175914.5. This variant is absent in gnomAD v2.1.1 (PM2_Supporting) and is predicted to be deleterious by computational evidence, with a REVEL score of 0.979​, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in seven unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:23771925, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and response to low-dose SU ) (PP4_Moderate; internal lab contributors). This variant was segregated with diabetes, with three informative meioses in two families (PP1_Moderate; internal lab contributors). In summary, c.733G>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PS4, PP1_moderate, PP3, PP4_moderate, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA409107461/MONDO:0015967/085

Frequency

Genomes: not found (cov: 32)

Consequence

HNF4A
NM_175914.5 missense

Scores

16
2
1

Clinical Significance

Pathogenic reviewed by expert panel P:2U:1

Conservation

PhyloP100: 8.01
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PP1
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.
PP4
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HNF4ANM_175914.5 linkuse as main transcriptc.740T>C p.Leu247Pro missense_variant 7/10 ENST00000316673.9 NP_787110.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HNF4AENST00000316673.9 linkuse as main transcriptc.740T>C p.Leu247Pro missense_variant 7/101 NM_175914.5 ENSP00000315180 P41235-5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2Uncertain:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Monogenic diabetes Pathogenic:1
Pathogenic, reviewed by expert panelcurationClinGen Monogenic Diabetes Variant Curation Expert PanelAug 30, 2024The c.740T>C variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of leucine to proline at codon 247 (p.(Leu247Pro)) of NM_175914.5. This variant is absent in gnomAD v2.1.1 (PM2_Supporting) and is predicted to be deleterious by computational evidence, with a REVEL score of 0.979, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in seven unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:23771925, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and response to low-dose SU ) (PP4_Moderate; internal lab contributors). This variant was segregated with diabetes, with three informative meioses in two families (PP1_Moderate; internal lab contributors). In summary, c.733G>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PS4, PP1_moderate, PP3, PP4_moderate, PM2_Supporting. -
Maturity-onset diabetes of the young type 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoApr 29, 2016- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJun 25, 2020Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Identified in one patient with maturity onset diabetes of the young, however, family segregation and functional studies were not performed; please note that this variant is reported using alternate nomenclature L260P (Pihoker et al., 2013); This variant is associated with the following publications: (PMID: 23771925) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.57
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.53
.;.;.;D;.;D;.
Eigen
Pathogenic
0.85
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D;D;D
M_CAP
Pathogenic
0.87
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.1
.;.;.;.;H;H;H
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Pathogenic
0.80
T
PROVEAN
Pathogenic
-5.8
D;.;D;.;D;D;D
REVEL
Pathogenic
0.98
Sift
Pathogenic
0.0
D;.;D;.;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D;D;D;D
Polyphen
1.0
.;D;D;.;D;D;.
Vest4
0.99
MutPred
0.88
.;.;.;.;Loss of stability (P = 0.02);Loss of stability (P = 0.02);Loss of stability (P = 0.02);
MVP
0.99
MPC
1.3
ClinPred
1.0
D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.98
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555816654; hg19: chr20-43048430; API