rs1280663753

chr20-44414547-CGAA-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM4_Supporting PP3 PP5

The NM_175914.5(HNF4A):c.473_475del(p.Lys158del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A156A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HNF4A NM_175914.5 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 O:1
• Conservation: PhyloP100: 9.32

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_175914.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_175914.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 20-44414547-CGAA-C is Pathogenic according to our data. Variant chr20-44414547-CGAA-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435437.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_risk_allele=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF4A	NM_175914.5	c.473_475del	p.Lys158del	inframe_deletion	5/10	ENST00000316673.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF4A	ENST00000316673.9	c.473_475del	p.Lys158del	inframe_deletion	5/10	1	NM_175914.5

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000416

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Maturity onset diabetes mellitus in young Pathogenic:1 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 19, 2022	Variant summary: HNF4A c.473_475delAGA (p.Lys158del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant was absent in 251470 control chromosomes. c.473_475delAGA has been reported in the literature as an assumed de-novo variant in at-least one 16 year old individual affected with Maturity Onset Diabetes Of The Young 1 who underwent analysis for 7 prominent MODY genes and exhibited characteristic elevations in fasting glucose and Hemoglobin A1c levels (example, Ozdemir_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Uncertain risk allele, criteria provided, single submitter	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	-	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 rs1280663753 in MODY, yet. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 11, 2017

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1280663753; hg19: chr20-43043187;