NM_000545.8:c.-218T>C
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_000545.8(HNF1A):c.-218T>C variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.0000114 in 615,748 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
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HNF1A | NM_000545.8 | c.-218T>C | 5_prime_UTR_variant | Exon 1 of 10 | ENST00000257555.11 | NP_000536.6 | ||
HNF1A | NM_001306179.2 | c.-218T>C | 5_prime_UTR_variant | Exon 1 of 10 | NP_001293108.2 | |||
HNF1A | NM_001406915.1 | c.-218T>C | 5_prime_UTR_variant | Exon 1 of 9 | NP_001393844.1 | |||
HNF1A | XM_024449168.2 | c.-218T>C | 5_prime_UTR_variant | Exon 1 of 9 | XP_024304936.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HNF1A | ENST00000257555 | c.-218T>C | 5_prime_UTR_variant | Exon 1 of 10 | 1 | NM_000545.8 | ENSP00000257555.5 |
Frequencies
GnomAD3 genomes AF: 0.0000198 AC: 3AN: 151774Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000862 AC: 4AN: 463974Hom.: 0 Cov.: 3 AF XY: 0.0000121 AC XY: 3AN XY: 247354
GnomAD4 genome AF: 0.0000198 AC: 3AN: 151774Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74102
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant summary: HNF1A c.-218T>C is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 1.1e-05 in 615748 control chromosomes, predominantly at a frequency of 1.1e-05 within the Non-Finnish European subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.-218T>C has been reported in the literature in at least 1 individual affected with Maturity Onset Diabetes Of The Young 3 (example, Godart_2000). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on gene expression. The most pronounced variant effect results in >50%-90% of normal gene expression in vitro (example, Godart_2000). The following publication have been ascertained in the context of this evaluation (PMID: 10649494). ClinVar contains an entry for this variant (Variation ID: 1327603). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Monogenic diabetes Uncertain:1
The c.-218T>C variant in the HNF1 homeobox 1 gene, HNF1A gene, is a single nucleotide variant within the promoter region of NM_000545.8. This variant is located within the overlapping HNF3 and NF-Y sites (c.-209 to c.-227) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant was identified in five unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (internal lab contributors); however, PS4 cannot be applied because the frequency of the c.-218T>C variant is 0.0000319 in gnomAD v2.1.1, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither PM2_Supporting, BS1, nor PS4_moderate can be applied. Additionally, functional studies demonstrated the variant has transactivation activity at 70% of wildtype, suggesting that this variant does not impact protein function, however sufficient controls were not used per MDEP guidelines and therefore BS3 cannot be applied (PMID: 10649494). Taken together, this evidence supports the classification of this variant as a variant of uncertain significance. ACMP/AMP criteria applied, as specified by the ClinGen MDEP VCEP: PM1_Supporting (specification version 1.0). -
HNF1A-related disorder Uncertain:1
The HNF1A c.-218T>C variant is located in the 5' untranslated region. This variant has been previously reported in one individual with maturity onset diabetes of the young (MODY) (Godart et al. 2000. PubMed ID: 10649494). An in vitro assay found that the c.-218T>C variant had a roughly 30% reduction in transcriptional activity compared to a wild-type construct (Godart et al 2000. PubMed ID: 10649494). However, no family studies were performed to help assess the pathogenicity of this variant. This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is classified as uncertain significance by ClinGen Monogenic Diabetes Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/1327603/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at