20-44355866-G-A
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_175914.5(HNF4A):c.49+13G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,608,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_175914.5 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HNF4A | ENST00000316673.9 | c.49+13G>A | intron_variant | Intron 1 of 9 | 1 | NM_175914.5 | ENSP00000315180.4 | |||
HNF4A | ENST00000457232.5 | c.49+13G>A | intron_variant | Intron 1 of 9 | 1 | ENSP00000396216.1 | ||||
HNF4A | ENST00000609795.5 | c.49+13G>A | intron_variant | Intron 1 of 7 | 1 | ENSP00000476609.1 | ||||
HNF4A | ENST00000609262.5 | c.-183+13G>A | intron_variant | Intron 1 of 3 | 1 | ENSP00000476310.1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152200Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000406 AC: 1AN: 246082Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 133904
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1456628Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 723872
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152200Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74350
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant summary: HNF4A c.49+13G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.1e-06 in 246082 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.49+13G>A in individuals affected with Maturity Onset Diabetes of The Young 1/Neonatal Diabetes Mellitus and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Maturity onset diabetes mellitus in young Benign:1
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 rs759324522 in MODY, yet. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at