rs1555813319

chr20-44406208-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_175914.5(HNF4A):c.200G>A(p.Arg67Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R67W) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: HNF4A NM_175914.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5 U:1
• Conservation: PhyloP100: 9.92

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_175914.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-44406207-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2736967.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958
• PP5: Variant 20-44406208-G-A is Pathogenic according to our data. Variant chr20-44406208-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 435436.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr20-44406208-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF4A	NM_175914.5	c.200G>A	p.Arg67Gln	missense_variant	2/10	ENST00000316673.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF4A	ENST00000316673.9	c.200G>A	p.Arg67Gln	missense_variant	2/10	1	NM_175914.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461428 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727020

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; No data available from control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 21353246, 20705777, 31523701, 29493090, 30977832) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 30, 2021	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. This variant appears to segregate with disease in at least one family, however, the available information does not rule out segregation due to chance. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. This variant is also referred to as p.R80Q or p.R67Q in published literature. Computational tools predict that this variant is damaging. -

Maturity onset diabetes mellitus in young Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 20, 2022

Variant summary: HNF4A c.200G>A (p.Arg67Gln) results in a conservative amino acid change located in the Zinc finger, nuclear hormone receptor-type domain (IPR001628) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250358 control chromosomes (gnomAD). c.200G>A (also known as p.R80Q) has been reported in the literature in multiple individuals affected with neonatal hyperinsulinism, macrosomia, and diabetes (examples: Forlani_2010, Pingul_2011 and Johannsson_2012). These data indicate that the variant is very likely to be associated with disease. Another variant affecting the same amino acid (p.R67W) is associated with MODY in HGMD. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Monogenic diabetes Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Apr 05, 2024

The c.200G>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to glutamine at codon 67 (p.(Arg67Gln)) of NM_175914.5. This variant has poor data quality in gnomAD v2.1.1 exomes but is absent in gnomAD genomes v3.0 and therefore at the discretion of the ClinGen MDEP PM2_Supporting will be applied (PM2_Supporting). This variant was identified in 17 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:31523701, 20705777, 21353246, 29493090, internal lab contributors). At least 3 of these individuals has a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative antibodies) (PP4_Moderate; PMID:20705777, internal lab contributors). This variant segregated with diabetes/hyperglycemia, with at least 10 informative meioses in five families (PP1_Strong; PMID:20705777, internal lab contributor). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.943, which is greater than the MDEP VCEP threshold of 0.70 (PP3). It resides in an amino acid within the HNF4alpha DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). Another missense variant, c.199C>T (p.(Arg67Trp)), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.(Arg67Gln) (PM5_Supporting). In summary, the c.200G>A variant 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, PM1, PP3, PM2_Supporting, PM5_Supporting. -

Hyperinsulinism due to HNF4A deficiency Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 22, 2015

- -

Maturity-onset diabetes of the young type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Geisinger Clinic, Geisinger Health System

Aug 02, 2022

PS4, PM2, PP3, PP1_Strong, PP4_Moderate, PM1, PM5_Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Pathogenic	35
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.6	D;.;D;.;.;D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.;D;.;.;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;T;D;D;D
Polyphen		1.0, 1.0	.;D;D;.;.;D;D;.
Vest4		0.93
MutPred		0.81		.;.;.;.;.;Loss of MoRF binding (P = 0.0487);Loss of MoRF binding (P = 0.0487);Loss of MoRF binding (P = 0.0487);
MVP		1.0
MPC		1.5
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.97
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs1555813319; hg19: chr20-43034848; COSMIC: COSV57385421; COSMIC: COSV57385421;