rs193922578

chr12-120978893-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000545.8(HNF1A):c.130del(p.Leu44TrpfsTer111) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. G42G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1A NM_000545.8 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: -0.174

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

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-120978893-GC-G is Pathogenic according to our data. Variant chr12-120978893-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 36798.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1A	NM_000545.8	c.130del	p.Leu44TrpfsTer111	frameshift_variant	1/10	ENST00000257555.11
HNF1A	NM_001306179.2	c.130del	p.Leu44TrpfsTer111	frameshift_variant	1/10
HNF1A	NM_001406915.1	c.130del	p.Leu44TrpfsTer111	frameshift_variant	1/9
HNF1A	XM_024449168.2	c.130del	p.Leu44TrpfsTer111	frameshift_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11	c.130del	p.Leu44TrpfsTer111	frameshift_variant	1/10	1	NM_000545.8	P4
HNF1A-AS1	ENST00000619441.1	n.128+1750del		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Maturity onset diabetes mellitus in young Pathogenic:2

Likely pathogenic, criteria provided, single submitter	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	-	Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. However, more evidence is required to confer the association of this particular variant rs193922578 with MODY3. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 23, 2019	The c.130delC pathogenic mutation, located in coding exon 1 of the HNF1A gene, results from a deletion of one nucleotide at nucleotide position 130, causing a translational frameshift with a predicted alternate stop codon (p.L44Wfs*111). This mutation was identified in multiple individuals from two maturity-onset diabetes of the young families (Klupa T et al. Diabetes Care, 2002 Dec;25:2292-301; McKinney JL et al. Clin Invest Med, 2004 Jun;27:135-41). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Monogenic diabetes Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Apr 02, 2022

The c.130delC variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 44 (NM_000545.8), adding 111 novel amino acids before encountering a stop codon (p.(Leu44TrpfsTer111)). This variant, located in biologically-relevant exon 1 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805) and is absent from gnomAD v2.1.1 (PM2_Supporting). 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) (PP4; PMID: 15305805). This variant segregated with diabetes, with at least five informative meioses in two families with MODY (PP1_Strong; PMIDs: 15305805 and 12453976). This variant was Identified in 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 (PMIDs: 15305805 and 12453976). In summary, c.130delC meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PVS1, PM2_Supporting, PP1_Strong, PP4. -

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

Pathogenic, criteria provided, single submitter

clinical testing;curation

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 18, 2011

- -

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

LitVar

Other links and lift over

dbSNP: rs193922578; hg19: chr12-121416696;