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NM_175914.5(HNF4A):c.421del (p.Arg141fs) AND Monogenic diabetes

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Apr 5, 2024
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV003993723.1

Allele description [Variation Report for NM_175914.5(HNF4A):c.421del (p.Arg141fs)]

NM_175914.5(HNF4A):c.421del (p.Arg141fs)

Gene:
HNF4A:hepatocyte nuclear factor 4 alpha [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
20q13.12
Genomic location:
Preferred name:
NM_175914.5(HNF4A):c.421del (p.Arg141fs)
Other names:
NM_175914.5:c.421del
HGVS:
  • NC_000020.11:g.44413795del
  • NG_009818.1:g.62995del
  • NM_000457.6:c.487del
  • NM_001030003.3:c.421del
  • NM_001030004.3:c.421del
  • NM_001258355.2:c.466del
  • NM_001287182.2:c.412del
  • NM_001287183.2:c.412del
  • NM_001287184.2:c.412del
  • NM_175914.5:c.421delMANE SELECT
  • NM_178849.3:c.487del
  • NM_178850.3:c.487del
  • NP_000448.3:p.Arg163Aspfs
  • NP_000448.3:p.Arg163fs
  • NP_001025174.1:p.Arg141fs
  • NP_001025175.1:p.Arg141fs
  • NP_001245284.1:p.Arg156fs
  • NP_001274111.1:p.Arg138fs
  • NP_001274112.1:p.Arg138Aspfs
  • NP_001274112.1:p.Arg138fs
  • NP_001274113.1:p.Arg138fs
  • NP_787110.2:p.Arg141Aspfs
  • NP_787110.2:p.Arg141fs
  • NP_849180.1:p.Arg163fs
  • NP_849181.1:p.Arg163fs
  • LRG_483t1:c.421del
  • LRG_483t2:c.487del
  • LRG_483t3:c.412del
  • LRG_483:g.62995del
  • LRG_483p1:p.Arg141Aspfs
  • LRG_483p2:p.Arg163Aspfs
  • LRG_483p3:p.Arg138Aspfs
  • NC_000020.10:g.43042435del
  • NM_000457.4:c.487delC
  • NM_001287183.1:c.412delC
  • NM_175914.4:c.421delC
Protein change:
R138fs
Molecular consequence:
  • NM_000457.6:c.487del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001030003.3:c.421del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001030004.3:c.421del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001258355.2:c.466del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001287182.2:c.412del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001287183.2:c.412del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001287184.2:c.412del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_175914.5:c.421del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_178849.3:c.487del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_178850.3:c.487del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:
Monogenic diabetes
Identifiers:
MONDO: MONDO:0015967; MedGen: C3888631

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004812232ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(ClinGen Diabetes ACMG Specifications HNF4A V2.0.0)		Pathogenic
(Apr 5, 2024) 		germlinecuration

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From ClinGen Monogenic Diabetes Variant Curation Expert Panel, SCV004812232.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.421del variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes a frameshift in the protein at codon 141 of NM_175914.5, adding 29 novel amino acids before encountering a stop codon (p.(Arg141AspfsTer29)). This variant, located in biologically-relevant exon 4 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in an individual with a clinical history suggestive of HNF4A-MODY (neonatal hyperinsulinemic hypoglycemia that is responsive to diazoxide and negative genetic testing for ABCC8 and KCNJ11)(PP4; PMID: 23796040). This variant segregated with diabetes, with three informative meioses in a single family with MODY (PP1; internal lab contributor). In summary, c.421del 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 10/11/23): PVS1, PP1, PP4, PM2_Supporting.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Apr 20, 2024