rs1280663753

Variant names:

• chr20-44414547-CGAA-C
• rs1280663753
• NM_175914.5:c.473_475delAGA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2_Supporting PM4_Supporting

This summary comes from the ClinGen Evidence Repository: The c.473_475del variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, is a three base pair deletion resulting in the in-frame deletion of one amino acid at codon 158 (p.(Lys158del)) within exon 5 of NM_174914.5. The c.473_475del variant is predicted to change the length of the protein due to an in-frame deletion of a single amino acid in a nonrepeat region (PM4_Supporting). Additionally, this variant is absent in gnomAD v2.1.1 (PM2_Supporting). In summary, c.473_475del meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PM2_Supporting, PM4_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA645373276/MONDO:0015967/085

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HNF4A NM_175914.5 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:1 O:1
• Conservation: PhyloP100: 9.32
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM4: 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.473_475delAGA	p.Lys158del	disruptive_inframe_deletion	Exon 5 of 10	NP_787110.2
	HNF4A	NM_000457.6		c.539_541delAGA	p.Lys180del	disruptive_inframe_deletion	Exon 5 of 10	NP_000448.3
	HNF4A	NM_001258355.2		c.518_520delAGA	p.Lys173del	disruptive_inframe_deletion	Exon 6 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.473_475delAGA	p.Lys158del	disruptive_inframe_deletion	Exon 5 of 10	ENSP00000315180.4	P41235-5
	HNF4A	ENST00000316099.10	TSL:1	c.539_541delAGA	p.Lys180del	disruptive_inframe_deletion	Exon 5 of 10	ENSP00000312987.3	P41235-1
	HNF4A	ENST00000415691.2	TSL:1	c.539_541delAGA	p.Lys180del	disruptive_inframe_deletion	Exon 5 of 10	ENSP00000412111.1	P41235-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461882 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

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

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3
Mutation Taster		=48/52	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: rs1280663753; hg19: chr20-43043187;