12-120978572-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.-197C>T variant in the HNF1 homeobox A gene, HNF1A, is a single nucleotide variant within the 5' UTR of NM_000545.8. This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). Additionally, PP4 cannot be applied as the calculated MODY probability is <50% (internal lab contributors). In summary, c.-197C>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 08/11/2023): PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA2797727079/MONDO:0015967/017

Frequency

Genomes: not found (cov: 32)

Consequence

HNF1A
NM_000545.8 5_prime_UTR

Scores

2

Clinical Significance

Uncertain significance reviewed by expert panel U:1

Conservation

PhyloP100: 2.59
Variant links:
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]
HNF1A-AS1 (HGNC:26785): (HNF1A antisense RNA 1)

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HNF1ANM_000545.8 linkc.-197C>T 5_prime_UTR_variant Exon 1 of 10 ENST00000257555.11 NP_000536.6 P20823E0YMI7
HNF1ANM_001306179.2 linkc.-197C>T 5_prime_UTR_variant Exon 1 of 10 NP_001293108.2 P20823E0YMI7
HNF1ANM_001406915.1 linkc.-197C>T 5_prime_UTR_variant Exon 1 of 9 NP_001393844.1
HNF1AXM_024449168.2 linkc.-197C>T 5_prime_UTR_variant Exon 1 of 9 XP_024304936.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HNF1AENST00000257555 linkc.-197C>T 5_prime_UTR_variant Exon 1 of 10 1 NM_000545.8 ENSP00000257555.5 A0A0A0MQU7

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
3
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Monogenic diabetes Uncertain:1
Feb 28, 2025
ClinGen Monogenic Diabetes Variant Curation Expert Panel
Significance: Uncertain significance
Review Status: reviewed by expert panel
Collection Method: curation

The c.-197C>T variant in the HNF1 homeobox A gene, HNF1A, is a single nucleotide variant within the 5' UTR of NM_000545.8. This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). Additionally, PP4 cannot be applied as the calculated MODY probability is <50% (internal lab contributors). In summary, c.-197C>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 08/11/2023): PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.26
CADD
Benign
21
DANN
Benign
0.93
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.3

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-121416375; API