chr12-121001053-TTGCCTCTGCAG-T

Variant names:

• chr12-121001053-TTGCCTCTGCAG-T
• NM_022895.3:c.*3089_*3099delCTGCAGAGGCA

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000545.8(HNF1A):​c.1769-9_1770delCCTCTGCAGTG​(p.Ser591fs) variant causes a frameshift, splice acceptor, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HNF1A NM_000545.8 frameshift, splice_acceptor, splice_region, intron
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1
• Conservation: PhyloP100: 7.86

Genes affected

C12orf43 (HGNC:25719): (chromosome 12 open reading frame 43) Predicted to be involved in Spemann organizer formation and negative regulation of Wnt signaling pathway. Predicted to be located in nuclear envelope. [provided by Alliance of Genome Resources, Apr 2022]

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 9 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-121001053-TTGCCTCTGCAG-T is Pathogenic according to our data. Variant chr12-121001053-TTGCCTCTGCAG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3370444.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C12orf43	NM_022895.3	c.*3089_*3099delCTGCAGAGGCA		3_prime_UTR_variant	Exon 6 of 6	ENST00000288757.7	NP_075046.1
HNF1A	NM_000545.8	c.1769-9_1770delCCTCTGCAGTG	p.Ser591fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 10 of 10	ENST00000257555.11	NP_000536.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C12orf43	ENST00000288757	c.*3089_*3099delCTGCAGAGGCA		3_prime_UTR_variant	Exon 6 of 6	1	NM_022895.3	ENSP00000288757.5
HNF1A	ENST00000257555.11	c.1769-9_1770delCCTCTGCAGTG	p.Ser591fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 10 of 10	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:1

Oct 13, 2024

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1769-9_1770del variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a splice acceptor site in intron 9 of NM_000545.8. Given the predicted loss of the intron 9 acceptor site, this variant is predicted to result in the loss of exon 10 and to disrupt a significant part of the transactivation domain, a functionally important region of the protein. Even though this truncated transcript is predicted to escape nonsense mediated decay in a gene in which loss-of-function is an established mechanism of disease, there is clinical evidence that variants in this region lead to a monogenic diabetes phenotype. (PVS1_Strong; PMID: 23348805). This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). Additionally, 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, and sensitive to sulfonyureas) (PP4_Moderate; internal lab contributors). In summary, c.1769-9_1770del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.1, approved 8/11/2023): PVS1_Strong, PM2_Supporting, PP4_Moderate). -

Computational scores

Source: dbNSFP v4.3

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: chr12-121438856;