12-120978551-T-C
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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
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000086 ( 0 hom. )
Consequence
HNF1A
NM_000545.8 5_prime_UTR
NM_000545.8 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 4.05
Genes affected
HNF1A (HGNC:11621): (HNF1 homeobox A) The protein encoded by this gene is a transcription factor required for the expression of several liver-specific genes. The encoded protein functions as a homodimer and binds to the inverted palindrome 5'-GTTAATNATTAAC-3'. Defects in this gene are a cause of maturity onset diabetes of the young type 3 (MODY3) and also can result in the appearance of hepatic adenomas. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.29).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HNF1A | NM_000545.8 | c.-218T>C | 5_prime_UTR_variant | 1/10 | ENST00000257555.11 | ||
HNF1A | NM_001306179.2 | c.-218T>C | 5_prime_UTR_variant | 1/10 | |||
HNF1A | NM_001406915.1 | c.-218T>C | 5_prime_UTR_variant | 1/9 | |||
HNF1A | XM_024449168.2 | c.-218T>C | 5_prime_UTR_variant | 1/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HNF1A | ENST00000257555.11 | c.-218T>C | 5_prime_UTR_variant | 1/10 | 1 | NM_000545.8 | P4 | ||
HNF1A-AS1 | ENST00000619441.1 | n.128+2093A>G | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000198 AC: 3AN: 151774Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000862 AC: 4AN: 463974Hom.: 0 Cov.: 3 AF XY: 0.0000121 AC XY: 3AN XY: 247354
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GnomAD4 genome AF: 0.0000198 AC: 3AN: 151774Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74102
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Monogenic diabetes Uncertain:1
Uncertain significance, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | Aug 11, 2021 | 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
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 11, 2023 | The HNF1A c.-218T>C variant is located in the 5' untranslated region. This variant was 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. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at