chr12-120978705-CACGCGGTGG-GC

Variant names:

• chr12-120978705-CACGCGGTGG-GC
• ENST00000538626.2:n.55_64delCACGCGGTGGinsGC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000538626.2(HNF1A):​n.55_64delCACGCGGTGGinsGC variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: HNF1A ENST00000538626.2 non_coding_transcript_exon
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.73
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.-64_-55delCACGCGGTGGinsGC		5_prime_UTR_variant	Exon 1 of 10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.-64_-55delCACGCGGTGGinsGC		5_prime_UTR_variant	Exon 1 of 10		NP_001293108.2
HNF1A	NM_001406915.1	c.-64_-55delCACGCGGTGGinsGC		5_prime_UTR_variant	Exon 1 of 9		NP_001393844.1
HNF1A	XM_024449168.2	c.-64_-55delCACGCGGTGGinsGC		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	ENST00000257555.11	c.-64_-55delCACGCGGTGGinsGC		5_prime_UTR_variant	Exon 1 of 10	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Diabetes mellitus type 1;C0011860:Type 2 diabetes mellitus;C1838100:Maturity-onset diabetes of the young type 3;C1840646:Hepatic adenomas, familial;C2675866:Type 1 diabetes mellitus 20;CN074294:Nonpapillary renal cell carcinoma Pathogenic:1

May 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Sep 15, 2023

Department of Medical Genomics, Royal Prince Alfred Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This insertion-deletion in the 5' untranslated region of HNF1A was detected in a patient with early onset (<30 years old), atypical diabetes with a family history. HbA1c was 9% at presentation. This indel is a rare variant not detected in control population database (gnomAD v.2.1.1). The indel was reported in two independent MODY3 families, and segregated with phenotype. In vitro functional studies showed that the indel causes a reduction in HNF1A promoter activity. Other promoter variants in HNF1A have also been reported in patients with MODY3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.7
Mutation Taster		=18/282	disease causing

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr12-121416508;