rs776793516

Positions:

• chr12-120997491-GCA-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.1330_1331del​(p.Gln444GlufsTer104) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,124 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely risk allele (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HNF1A NM_000545.8 frameshift
• Clinical Significance: Pathogenic/Likely risk allele criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.90

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]

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 12-120997491-GCA-G is Pathogenic according to our data. Variant chr12-120997491-GCA-G is described in ClinVar as [Likely_risk_allele]. Clinvar id is 617650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_risk_allele=1, Pathogenic=7}. Variant chr12-120997491-GCA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.1330_1331del	p.Gln444GlufsTer104	frameshift_variant	7/10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.1330_1331del	p.Gln444GlufsTer111	frameshift_variant	7/10		NP_001293108.2
HNF1A	XM_024449168.2	c.1330_1331del	p.Gln444GlufsTer110	frameshift_variant	7/9		XP_024304936.1
HNF1A	NM_001406915.1	c.1309+752_1309+753del		intron_variant			NP_001393844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.1330_1331del	p.Gln444GlufsTer104	frameshift_variant	7/10	1	NM_000545.8	ENSP00000257555	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248382 Hom.: 0 AF XY: 0.00000743 AC XY: 1 AN XY: 134622

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458124 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 725324

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.: 32

ClinVar

Significance: Pathogenic/Likely risk allele

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Maturity onset diabetes mellitus in young Pathogenic:3

Likely risk allele, 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 rs776793516 with MODY3. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 30, 2020	The c.1330_1331delCA pathogenic mutation, located in coding exon 7 of the HNF1A gene, results from a deletion of two nucleotides at nucleotide positions 1330 to 1331, causing a translational frameshift with a predicted alternate stop codon (p.Q444Efs*104). This mutation has been identified in families with maturity onset diabetes of the young (Frayling TM et al. Hum. Genet., 1997 Dec;101:351-4; Delvecchio M et al. Diabetes Care, 2014 Dec;37:e258-60). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 06, 2020	The p.Gln444GlufsX104 variant in HNF1A has been reported in at least 3 families with maturity-onset diabetes of the young (MODY) and segregated with disease in at least 13 affected relatives from 2 families (Frayling 1997 PMID: 9439666, Frayling 2001 PMID: 11272211, Delvecchio 2014 PMID: 25414397, Frayling 1997 PMID: 9075818, Klupa 2002 PMID: 12453976). This variant has also been reported in ClinVar (Variation ID 617650) and identified in 1/112510 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 444 and leads to a premature termination codon 104 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the HNF1A gene is an established disease mechanism in autosomal dominant MODY. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant MODY. ACMG/AMP Criteria applied: PM2, PVS1, PS4_Supporting, PP1_Strong. -

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

Pathogenic, criteria provided, single submitter	research	Geisinger Clinic, Geisinger Health System	Aug 02, 2022	PVS1, PM2, PP4_Moderate, PS4_Moderate, PP1 -
Pathogenic, criteria provided, single submitter	clinical testing	Translational Genomics Laboratory, University of Maryland School of Medicine	Apr 17, 2018	The c.1328_1329delCA variant in the HNF1A homeobox A gene, HNF1A, results in a frame shifting change in the protein with the Glutamine at codon 444 (exon 7) being the first affected amino acid. Frameshift mutations in the HNF1A gene, including ones in exon 7, have been reported previously in patients with a clinical picture consistent with Maturity-Onset Diabetes of the Young, Type 3 (MODY3) (23348805, 9439666, 11272211, 18003757). The c.1328_1329delCA variant has been previously identified in multiple individuals with MODY3 (9439666, 11272211, 25414397, 9075818, 12453976), with evidence of familial segregation in three families (11272211, 9075818, 12453976). This result is also consistent with the clinical diagnosis of MODY in multiple paternal family members. ACMG criteria = PVS1, PS4-mod, PP1-mod -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Gln444Glufs variant in HNF1a has been reported in 5 families with maturity-onset diabetes of the young type 3 (MODY3) and has been identified in 0.0008888% (1/112510) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs776793516). This variant has also been reported in ClinVar (VariationID: 617650) as pathogenic by the Translational Genomics Laboratory. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 444 and leads to a premature termination codon 104 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the HNF1A gene is an established disease mechanism in MODY3. In summary, this variant meets criteria to be classified as pathogenic for MODY3 in an autosomal dominant manner based on the prediction that it causes loss of function of the HNF1A gene and the increased prevalence of the variant in affected individuals compared with controls. ACMG/AMP Criteria applied: PVS1, PM2, PS4_supporting (Richards 2015). -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 09, 2022	For these reasons, this variant has been classified as Pathogenic. This variant is also known as A443fsdelCA. This premature translational stop signal has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 9439666, 25414397). This variant is present in population databases (rs776793516, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Gln444Glufs*104) in the HNF1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HNF1A are known to be pathogenic (PMID: 15928245, 18003757). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2022	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9439666, 23348805, 18003757, 11272211, 9075818, 12453976, 34789499, 25414397) -

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: rs776793516; hg19: chr12-121435294;