12-121001097-TC-T

Position:

• chr12-121001097-TC-T

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.1802delC​(p.Ser601fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000137 in 1,461,580 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HNF1A NM_000545.8 frameshift
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 4.61

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]

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]

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 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-121001097-TC-T is Pathogenic according to our data. Variant chr12-121001097-TC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1687084.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.1802delC	p.Ser601fs	frameshift_variant	10/10	ENST00000257555.11	NP_000536.6
C12orf43	NM_022895.3	c.*3055delG		3_prime_UTR_variant	6/6	ENST00000288757.7	NP_075046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.1802delC	p.Ser601fs	frameshift_variant	10/10	1	NM_000545.8	ENSP00000257555.5
C12orf43	ENST00000288757.7	c.*3055delG		3_prime_UTR_variant	6/6	1	NM_022895.3	ENSP00000288757.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461580 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727078

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

May 04, 2022

The c.1802del variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 601 (p.(Ser601Ter)) of NM_000545.8. While this variant, located 5' of c.1803 in exon 10 of 10, is not predicted to result in nonsense mediated decay of the transcript, it will significantly disrupt the transactivation domain of the protein (PVS1_Strong). Additionally, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and antibody negative) (PP4_Moderate; internal lab contributors) and is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in a total of 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). In summary, c.1802del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PVS1_Strong, PP4_Moderate, PM2_Supporting. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 12, 2023

Nonsense variant predicted to result in protein truncation as the last 31 amino acids are lost; other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr12-121438900;