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NM_175914.5(HNF4A):c.408G>A (p.Ala136=) AND Monogenic diabetes

Germline classification:
Likely benign (1 submission)
Last evaluated:
Jan 12, 2023
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:
RCV003126918.1

Allele description [Variation Report for NM_175914.5(HNF4A):c.408G>A (p.Ala136=)]

NM_175914.5(HNF4A):c.408G>A (p.Ala136=)

Gene:
HNF4A:hepatocyte nuclear factor 4 alpha [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
20q13.12
Genomic location:
Preferred name:
NM_175914.5(HNF4A):c.408G>A (p.Ala136=)
Other names:
NM_175914.5(HNF4A):c.408G>A; p.Ala136=
HGVS:
  • NC_000020.11:g.44413782G>A
  • NG_009818.1:g.62982G>A
  • NM_000457.6:c.474G>A
  • NM_001030003.3:c.408G>A
  • NM_001030004.3:c.408G>A
  • NM_001258355.2:c.453G>A
  • NM_001287182.2:c.399G>A
  • NM_001287183.2:c.399G>A
  • NM_001287184.2:c.399G>A
  • NM_175914.5:c.408G>AMANE SELECT
  • NM_178849.3:c.474G>A
  • NM_178850.3:c.474G>A
  • NP_000448.3:p.Ala158=
  • NP_000448.3:p.Ala158=
  • NP_001025174.1:p.Ala136=
  • NP_001025175.1:p.Ala136=
  • NP_001245284.1:p.Ala151=
  • NP_001274111.1:p.Ala133=
  • NP_001274112.1:p.Ala133=
  • NP_001274113.1:p.Ala133=
  • NP_787110.2:p.Ala136=
  • NP_849180.1:p.Ala158=
  • NP_849181.1:p.Ala158=
  • LRG_483t2:c.474G>A
  • LRG_483:g.62982G>A
  • LRG_483p2:p.Ala158=
  • NC_000020.10:g.43042422G>A
  • NC_000020.10:g.43042422G>A
  • NM_000457.4:c.474G>A
Links:
dbSNP: rs374298096
NCBI 1000 Genomes Browser:
rs374298096
Molecular consequence:
  • NM_000457.6:c.474G>A - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_001030003.3:c.408G>A - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_001030004.3:c.408G>A - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_001258355.2:c.453G>A - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_001287182.2:c.399G>A - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_001287183.2:c.399G>A - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_001287184.2:c.399G>A - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_175914.5:c.408G>A - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_178849.3:c.474G>A - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_178850.3:c.474G>A - synonymous variant - [Sequence Ontology: SO:0001819]

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
SCV003802725ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(MDEP HNF4A Specificiations 1.0.0)		Likely benign
(Jan 12, 2023) 		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, SCV003802725.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.408G>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, is a synonymous (silent) variant at codon 136 (p.(Ala136=)) of NM_175914.5. This variant is not predicted by SpliceAI to impact splicing (SpliceAI scores less than the MDEP cutoff of 0.2) and is not highly conserved (phyloP100way score of -1.087, which is below the MDEP cutoff of 2.0) (BP4, BP7). The Popmax frequency of the c.408G>A variant in gnomAD v2.1.1 is 0.00002619, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. In summary, c.408G>A meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0, approved 11/16/22): BP4, BP7.

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

Last Updated: May 7, 2024