chr20-44419742-G-A

Position:

• chr20-44419742-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP1_Strong PP3 PP4_Moderate PS4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.692G>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of arginine to glutamine at codon 231 (p.(Arg231Gln)) of NM_175914.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.896, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in 10 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:12413008, PMID:12627330, internal lab contributors). This variant segregated with diabetes, with at least four informative meioses in two families (PP1_Strong; PMID:12413008, internal lab contributor). One individual has a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, negative autoantibodies, and response to low-dose sulfonylureas) (PP4_Moderate; internal lab contributor). In summary, c.692G>A 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): PP1_Strong, PS4, PP4_Moderate, PP3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA409107360/MONDO:0015967/085

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HNF4A NM_175914.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 8.11

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 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
HNF4A	NM_175914.5	c.692G>A	p.Arg231Gln	missense_variant	7/10	ENST00000316673.9	NP_787110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF4A	ENST00000316673.9	c.692G>A	p.Arg231Gln	missense_variant	7/10	1	NM_175914.5	ENSP00000315180.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457874 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 725244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 13, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Also known as p.(Arg244Gln); This variant is associated with the following publications: (PMID: 12627330, 23227446, 12413008, 32971154, 36257325, 33242514) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 01, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 231 of the HNF4A protein (p.Arg231Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of maturity-onset diabetes of the young (PMID: 12413008, 12627330; Invitae). This variant is also known as p.Arg244Gln. ClinVar contains an entry for this variant (Variation ID: 447520). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HNF4A protein function. Experimental studies have shown that this missense change affects HNF4A function (PMID: 12413008). This variant disrupts the p.Arg231 amino acid residue in HNF4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 32418360, 36257325; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 20, 2016	- -

Monogenic diabetes Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

May 10, 2024

The c.692G>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of arginine to glutamine at codon 231 (p.(Arg231Gln)) of NM_175914.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.896, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in 10 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:12413008, PMID:12627330, internal lab contributors). This variant segregated with diabetes, with at least four informative meioses in two families (PP1_Strong; PMID:12413008, internal lab contributor). One individual has a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, negative autoantibodies, and response to low-dose sulfonylureas) (PP4_Moderate; internal lab contributor). In summary, c.692G>A 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): PP1_Strong, PS4, PP4_Moderate, PP3, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	.;.;.;T;.;D;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.0	.;.;.;.;M;M;M
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.0	D;.;D;.;D;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0020	D;.;D;.;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D;D;D;D
Polyphen		1.0, 1.0, 0.99	.;D;D;.;D;D;.
Vest4		0.72
MutPred		0.89		.;.;.;.;Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);
MVP		0.98
MPC		1.1
ClinPred		0.99	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.79
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555816615; hg19: chr20-43048382;