ENST00000316099:c.-106_-103delAAGG

Variant names:

• chr20-44401262-AAAGG-A
• rs886056679
• ENST00000316099:c.-106_-103delAAGG

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PM2_Supporting BP4

This summary comes from the ClinGen Evidence Repository: The c.50-4791_50-4788del variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, is a 4-nucleotide-deletion within intron 1 of NM_175914.5. The computational splicing predictor SpliceAI gives a score of 0.00 for donor and acceptor loss, suggesting that the variant has no impact on splicing (BP4). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.50-4791_50-4788del meets the criteria to be classified as VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): BP4, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10643872/MONDO:0015967/085

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: HNF4A ENST00000316099 5_prime_UTR
• Clinical Significance: Uncertain significance reviewed by expert panel U:3 B:1
• Conservation: PhyloP100: 4.59

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: 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.50-4791_50-4788delAAGG		intron_variant	Intron 1 of 9	ENST00000316673.9	NP_787110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF4A	ENST00000316673.9	c.50-4791_50-4788delAAGG		intron_variant	Intron 1 of 9	1	NM_175914.5	ENSP00000315180.4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151980 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000558 AC: 8 AN: 1433744 Hom.: 0 AF XY: 0.00000562 AC XY: 4 AN XY: 711662

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000726

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151980 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74234

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Maturity onset diabetes mellitus in young Uncertain:1 Benign:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Potent mutations in HNF4A are associated with poor insulin secretion in response to hyperglycemia. Associated with MODY1. Patients initially respond well to sulfonylureas but eventually become insulin dependent. However, more evidence is required to ascertain the role of this particular variant rs886056679 in MODY, yet. -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Monogenic diabetes Uncertain:1

Jan 29, 2025

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.50-4791_50-4788del variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, is a 4-nucleotide-deletion within intron 1 of NM_175914.5. The computational splicing predictor SpliceAI gives a score of 0.00 for donor and acceptor loss, suggesting that the variant has no impact on splicing (BP4). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.50-4791_50-4788del meets the criteria to be classified as VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): BP4, PM2_Supporting. -

Hyperinsulinism, Dominant Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs886056679; hg19: chr20-43029902;