NM_000545.8:c.-187C>T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_000545.8(HNF1A):c.-187C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000615 in 650,100 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 Uncertain significance (★★★).
Frequency
Consequence
NM_000545.8 5_prime_UTR_premature_start_codon_gain
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HNF1A | NM_000545.8 | c.-187C>T | 5_prime_UTR_premature_start_codon_gain_variant | Exon 1 of 10 | ENST00000257555.11 | NP_000536.6 | ||
HNF1A | NM_000545.8 | c.-187C>T | 5_prime_UTR_variant | Exon 1 of 10 | ENST00000257555.11 | NP_000536.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HNF1A | ENST00000257555 | c.-187C>T | 5_prime_UTR_premature_start_codon_gain_variant | Exon 1 of 10 | 1 | NM_000545.8 | ENSP00000257555.5 | |||
HNF1A | ENST00000257555 | c.-187C>T | 5_prime_UTR_variant | Exon 1 of 10 | 1 | NM_000545.8 | ENSP00000257555.5 |
Frequencies
GnomAD3 genomes AF: 0.00000659 AC: 1AN: 151828Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000113 AC: 1AN: 88876Hom.: 0 AF XY: 0.0000211 AC XY: 1AN XY: 47346
GnomAD4 exome AF: 0.00000602 AC: 3AN: 498272Hom.: 0 Cov.: 4 AF XY: 0.00000749 AC XY: 2AN XY: 266850
GnomAD4 genome AF: 0.00000659 AC: 1AN: 151828Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74122
ClinVar
Submissions by phenotype
Monogenic diabetes Uncertain:1
The c.-187C>T variant in the HNF1 homeobox A gene, HNF1A, is a single nucleotide variant within the promoter of NM_000545.8. This variant is located within the API binding site (c.-187 to c.-195) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). While c.-187C>T is absent in the European non-Finnish population in gnomAD v2.1.1, it has 2 copies in the African subpopulation; therefore, this variant does not meet the ClinGen MDEP-established cutoff for PM2_Supporting. This variant was identified in 4 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because the variant does not meet the PM2_Supporting cutoff (internal lab contributors). One of these individuals has a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea sensitive) (PP4_Moderate; internal lab contributor). Taken together, this criteria supports the classification of c.-187C>T as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0, approved): PP4_moderate, PM1_Supporting. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at