12-120978486-A-C

Variant names:

• chr12-120978486-A-C
• ENST00000433033.3:n.134+1128T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The ENST00000433033.3(HNF1A-AS1):​n.134+1128T>G 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 Likely pathogenic (★★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1A-AS1 ENST00000433033.3 intron
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 5.03

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-120978486-A-C is Pathogenic according to our data. Variant chr12-120978486-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14933.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.-283A>C		upstream_gene_variant		ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.-283A>C		upstream_gene_variant			NP_001293108.2
HNF1A	NM_001406915.1	c.-283A>C		upstream_gene_variant			NP_001393844.1
HNF1A	XM_024449168.2	c.-283A>C		upstream_gene_variant			XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.-283A>C		upstream_gene_variant		1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2

May 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant occurs in a non-coding region of the HNF1A gene. It does not change the encoded amino acid sequence of the HNF1A protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 9313764). It has also been observed to segregate with disease in related individuals. This variant is also known as A>C substitution at nucleotide -58. Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects HNF1A function (PMID: 10649494). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Mar 10, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate this variant has significantly decreased luciferase activity compared to wild-type (Godart et al., 2000; Lausen et al., 2000; Radha et al., 2009); No data available from control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 19336507, 10606640, 22413961, 23348805, 11692182, 10649494, 9313764) -

Monogenic diabetes Pathogenic:1

Aug 18, 2021

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.-283A>C in the HNF1 homeobox A gene, HNF1A, is a single nucleotide variant in the promoter of NM_000545.8. This variant is located within the HNF4A binding domain (c.-276 to c.-288) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Functional studies demonstrated the c.-283A>C protein has transactivation below 40% of wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMID:10649494). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), however it was identified in at least one individual with 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). This variant also segregated with diabetes, with 7 informative meioses in two families with MODY (PP1_Strong; PMID:9313764; internal lab contributor). Taken together, this evidence suggests the classification of this variant as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0_: PP1_Strong, PP4_moderate, PM1_Supporting, PM2_Supporting, PS3_Supporting). -

Maturity-onset diabetes of the young type 3 Pathogenic:1

Oct 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Benign	0.94

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: chr12-121416289;