rs1392795567

Variant names:

• chr20-44414663-G-A
• rs1392795567
• NM_175914.5:c.582+1G>A

Your query was ambiguous. Multiple possible variants found:

• chr20-44414663-G-A
• chr20-44414663-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP1 PM2_Supporting PVS1_Strong PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.582+1G>A variant in the hepatocyte nuclear factor-4 alpha gene, HNF4A, is predicted to remove a canonical splice donor site in intron 5 of NM_175914.5. This variant is predicted to cause an in-frame deletion of biologically relevant exon 5 of 10, removing more than 10% of the protein (PVS1_Strong). This variant failed QC in gnomAD v2.1.1 , is found in only one individual in BRAVO and absent from the Geisinger and UK Biobanks (PM2_Supporting). This variant was identified in at least 2 individuals with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, history of large for gestational age, and family history of persistent neonatal hypoglycemia) (PP4_Moderate; PMID:17407387, internal lab contributors). This variant segregated with diabetes, with 3 informative meioses in this family with MODY (PP1; PMID:17407387). In summary, c.582+1G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.1.0, approved 8/11/2023): PVS1_strong, PM2_supporting, PP4_moderate, PP1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA409106287/MONDO:0015967/085

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HNF4A NM_175914.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 10.0
• Publications: 1 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: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: 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.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF4A	NM_175914.5	c.582+1G>A		splice_donor_variant, intron_variant	Intron 5 of 9	ENST00000316673.9	NP_787110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF4A	ENST00000316673.9	c.582+1G>A		splice_donor_variant, intron_variant	Intron 5 of 9	1	NM_175914.5	ENSP00000315180.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 222894 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447886 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 718808

African (AFR) AF: 0.00 AC: 0 AN: 33330

American (AMR) AF: 0.0000241 AC: 1 AN: 41532

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25802

East Asian (EAS) AF: 0.00 AC: 0 AN: 39376

South Asian (SAS) AF: 0.00 AC: 0 AN: 84396

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105102

Other (OTH) AF: 0.00 AC: 0 AN: 59972

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2

Sep 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 5 of the HNF4A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HNF4A are known to be pathogenic (PMID: 20164212, 23275527, 23348805, 24097065). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of HNF4A-related conditions (PMID: 17407387). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS5nt + 1G>A. ClinVar contains an entry for this variant (Variation ID: 617652). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Jan 31, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 15830177, 23348805, 17407387, 29758564)

Maturity onset diabetes mellitus in young Pathogenic:1

Dec 17, 2020

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.582+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 5 of the HNF4A gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the missing amino acids is unknown; however, the impacted region is critical for protein function (Ambry internal data) and this alteration has been reported in a proband from a MODY cohort (Pearson ER et al. Diabetologia, 2005 May;48:878-85). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Monogenic diabetes Pathogenic:1

Sep 15, 2023

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.582+1G>A variant in the hepatocyte nuclear factor-4 alpha gene, HNF4A, is predicted to remove a canonical splice donor site in intron 5 of NM_175914.5. This variant is predicted to cause an in-frame deletion of biologically relevant exon 5 of 10, removing more than 10% of the protein (PVS1_Strong). This variant failed QC in gnomAD v2.1.1 , is found in only one individual in BRAVO and absent from the Geisinger and UK Biobanks (PM2_Supporting). This variant was identified in at least 2 individuals with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, history of large for gestational age, and family history of persistent neonatal hypoglycemia) (PP4_Moderate; PMID: 17407387, internal lab contributors). This variant segregated with diabetes, with 3 informative meioses in this family with MODY (PP1; PMID: 17407387). In summary, c.582+1G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.1.0, approved 8/11/2023): PVS1_strong, PM2_supporting, PP4_moderate, PP1.

Maturity-onset diabetes of the young type 1 Pathogenic:1

Nov 20, 2017

Translational Genomics Laboratory, University of Maryland School of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.573+1G>A variant in the Hepatocyte Nuclear Factor 4-Alpha gene, HNF4A, is predicted to remove a splice donor site in IVS7 (193395). Canonical splice site variants can often be assumed to disrupt gene function by leading to a complete absence of the gene product by lack of transcription or nonsense-mediated decay of an altered transcript. Splice site mutations in HNF4A, including ones in this intron, have been reported in patients with a clinical picture consistent with Maturity-Onset Diabetes of the Young, Type 1 (MODY1) (23348805). The c.573+1 G>A variant was not observed in the NHLBI Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium databases; however, the c.573+1 G>A variant was previously found to segregate with a MODY1 phenotype over three generations in one family (15830177, 17407387). Additionally, multiple lines of computational evidence (MutationTaster, FATHMM, GERP) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. ACMG criteria = PVS1, PM2, PP3, PP1

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;.;.;.;.;.;.
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.0	.;.;.;.;.;.;.
MetaRNN	Benign	0.0	.;.;.;.;.;.;.
MutationAssessor	Benign	0.0	.;.;.;.;.;.;.
PhyloP100		10
PROVEAN	Benign	0.0	.;.;.;.;.;.;.
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	.;.;.;.;.;.;.
Vest4		0.0
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.63		Position offset: 18
DS_DL_spliceai		1.0		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1392795567; hg19: chr20-43043303;