20-44419828-G-T

Variant names:

• chr20-44419828-G-T
• rs1236613475
• NM_175914.5:c.778G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP3 PM2_Supporting PS4_Moderate PP1_Moderate PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.778G>T variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of aspartate to tyrosine at codon 260 (p.(Asp260Tyr)) of NM_175914.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.912, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in 5 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; 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 antibody negative) (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.778G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PS4_moderate, PP1_moderate, PP4_moderate, PM2_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA409107542/MONDO:0015967/085

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF4A NM_175914.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:1
• Conservation: PhyloP100: 9.99
• Publications: 4 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

Specifications for HNF4A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_pathogenic. The variant received 8 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.

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.778G>T	p.Asp260Tyr	missense	Exon 7 of 10	NP_787110.2
	HNF4A	NM_000457.6		c.844G>T	p.Asp282Tyr	missense	Exon 7 of 10	NP_000448.3
	HNF4A	NM_001258355.2		c.823G>T	p.Asp275Tyr	missense	Exon 8 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.778G>T	p.Asp260Tyr	missense	Exon 7 of 10	ENSP00000315180.4	P41235-5
	HNF4A	ENST00000316099.10	TSL:1	c.844G>T	p.Asp282Tyr	missense	Exon 7 of 10	ENSP00000312987.3	P41235-1
	HNF4A	ENST00000415691.2	TSL:1	c.844G>T	p.Asp282Tyr	missense	Exon 7 of 10	ENSP00000412111.1	P41235-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	1	-	Monogenic diabetes (2)
-	-	-	Maturity-onset diabetes of the young (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		10
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-8.7	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.75		Gain of catalytic residue at I281 (P = 0.0229)
MVP		0.98
MPC		1.1
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.82
Mutation Taster		=22/78	disease causing

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: rs1236613475; hg19: chr20-43048468;