20-44424123-G-A

Variant names:

• chr20-44424123-G-A
• rs1375557127
• NM_175914.5:c.932G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PP3 PM2_Supporting PS4 PM1_Supporting PP1_Strong PM5_Supporting PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.932G>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of arginine to histidine at codon 311 (p.(Arg311His)) of NM_175914.5. This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to absence in the European non-Finnish subpopulation and 1 copy in the East Asian subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF GrpmaxPopmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.91​, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is located within the ligand-binding domain (codons 300-350) of HNF4A, which is defined as critical for the protein's function by the ClinGen MDEP (PM1_Supporting). This variant was identified in 7 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:25414397, 24947580 26059258, 32533152; internal lab contributors). This variant was identified in at least two individuals with a clinical history highly specific for HNF4A-MODY monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative antibodies; and family history of LGA/hypoglycemic infant) (PP4_Moderate; PMID:24947580, internal lab contributors). This variant segregated with diabetes, with 12 informative meioses in 4 families (PP1_Strong; PMIDs: 24947580, 26059258, 32533152, internal lab contributors). Another missense variant, p.(Arg311Cys), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.(Arg311His) (PM5_Supporting). In summary, c.932G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 10/11/2023): PM2_Supporting, PP3, PM1_Supporting, PS4, PP4_Moderate, PP1_Strong, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA409108268/MONDO:0015967/085

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: HNF4A NM_175914.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:9 U:3
• Conservation: PhyloP100: 10.0
• Publications: 11 publications found

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• 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

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175914.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF4A	NM_175914.5	MANE Select	c.932G>A	p.Arg311His	missense	Exon 8 of 10	NP_787110.2
	HNF4A	NM_000457.6		c.998G>A	p.Arg333His	missense	Exon 8 of 10	NP_000448.3
	HNF4A	NM_001258355.2		c.977G>A	p.Arg326His	missense	Exon 9 of 11	NP_001245284.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF4A	ENST00000316673.9	TSL:1 MANE Select	c.932G>A	p.Arg311His	missense	Exon 8 of 10	ENSP00000315180.4	P41235-5
	HNF4A	ENST00000316099.10	TSL:1	c.998G>A	p.Arg333His	missense	Exon 8 of 10	ENSP00000312987.3	P41235-1
	HNF4A	ENST00000415691.2	TSL:1	c.998G>A	p.Arg333His	missense	Exon 8 of 10	ENSP00000412111.1	P41235-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248800 AF XY: 0.00000741

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461130 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726854

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000448 AC: 2 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52868

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111922

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	1	-	Maturity-onset diabetes of the young type 1 (4)
2	1	-	not provided (3)
2	-	-	Maturity-onset diabetes of the young (2)
1	-	-	HNF4A-related disorder (1)
1	-	-	Monogenic diabetes (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		10
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.025	D
Sift4G	Benign	0.064	T
Polyphen		1.0	D
Vest4		0.93
MutPred		0.97		Loss of methylation at R333 (P = 0.0148)
MVP		0.99
MPC		1.1
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.68
gMVP		0.89
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1375557127; hg19: chr20-43052763; COSMIC: COSV57386667;