12-120978485-C-T

Variant names:

• chr12-120978485-C-T
• ENST00000433033.3:n.134+1129G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000433033.3(HNF1A-AS1):​n.134+1129G>A variant causes a intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HNF1A-AS1 ENST00000433033.3 intron
• Clinical Significance: Uncertain significance reviewed by expert panel U:1
• Conservation: PhyloP100: 3.93

Genes affected

HNF1A-AS1 (HGNC:26785): (HNF1A antisense RNA 1)

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.22).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.-284C>T		upstream_gene_variant		ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.-284C>T		upstream_gene_variant			NP_001293108.2
HNF1A	NM_001406915.1	c.-284C>T		upstream_gene_variant			NP_001393844.1
HNF1A	XM_024449168.2	c.-284C>T		upstream_gene_variant			XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.-284C>T		upstream_gene_variant		1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 359756 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 189662

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Uncertain:1

Jan 03, 2025

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.-284C>T variant in the HNF1 homeobox A gene, HNF1A, is a single nucleotide variant in the promoter region of NM_000545.8. This variant is located within the HNF4A binding site (–c.-276 to c.-288) of the promoter HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, negative antibodies, and >=3 generation family history of diabetes) (PP4_Moderate; internal lab contributors). In summary, c.-284C>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 8/11/2023): PP4_Moderate, PM1_Supporting, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Uncertain	0.98

Splicing

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: chr12-121416288;