12-120978770-T-C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_000545.8(HNF1A):c.2T>C(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1A NM_000545.8 start_lost
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 6.74

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 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000545.8 (HNF1A) was described as [Pathogenic] in ClinVar as 502525
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-120978770-T-C is Pathogenic according to our data. Variant chr12-120978770-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 1342949.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-120978770-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1A	NM_000545.8	c.2T>C	p.Met1?	start_lost	1/10	ENST00000257555.11
HNF1A	NM_001306179.2	c.2T>C	p.Met1?	start_lost	1/10
HNF1A	NM_001406915.1	c.2T>C	p.Met1?	start_lost	1/9
HNF1A	XM_024449168.2	c.2T>C	p.Met1?	start_lost	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11	c.2T>C	p.Met1?	start_lost	1/10	1	NM_000545.8	P4
HNF1A-AS1	ENST00000619441.1	n.128+1874A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Maturity onset diabetes mellitus in young Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 07, 2022	The p.Met1? (c.2T>C) variant in HNF1A has been reported in 1 individual with maturity-onset diabetes of the young (MODY) (Colclough 2013 PMID: 23348805). It was absent from large population studies. This variant was classified as Likely Pathogenic on Mar 4, 2022 by the ClinGen-approved Monogenic Diabetes expert panel (Variation ID 1342949). It affects the translation initiation start codon (ATG) and is therefore predicted to disrupt translation although a variety of outcomes (no protein synthesis or the activation of an downstream translation initiation codon) are possible. Additional variants involving the initiation codon (c.1A>C, c.1A>T) have been identified in individuals with MODY (Colclough 2013 PMID: 23348805, Bellanné-Chantelot 2008 PMID: 18003757), supporting that this change may not be tolerated. Loss of function of the HNF1A gene is an established disease mechanism in autosomal dominant MODY. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant MODY. ACMG/AMP Criteria applied: PVS1, PM2_P. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 08, 2016	The p.M1? variant (also known as c.2T>C), located in coding exon 1 of the HNF1A gene, results from a T to C substitution at nucleotide position 2. This alters the methionine residue at the initiation codon. This variant has been detected in three families with clinical diagnoses of MODY; however, specific phenotype information was not provided (Bellanné-Chantelot C, Diabetes 2008 Feb; 57(2):503-8; Colclough K, Hum. Mutat. 2013 May; 34(5):669-85.). Of note, the nucleotide changes observed in these studies, which all result in the same p.M1? alteration, include c.1A>C, c.1A>T, and c.2T>C. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6449 samples (12898 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation or N-terminal truncation, this alteration is interpreted as likely pathogenic (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Monogenic diabetes Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Aug 26, 2022

The c.2T>C variant in the HNF1 homeobox A gene, HNF1A, results in the loss of the initiation codon (p.Met1?) of NM_000545.8. By altering the start codon of the coding sequence, this variant is predicted to cause a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in at least 4 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 18003757, PMID: 23348805, internal lab contributors). One of these individuals had a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested, and PP4 was not applied (internal lab contributors). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors). In summary, c.2T>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2, approved 8/4/2022): PVS1, PS4_Moderate, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
Cadd	Benign	23
Dann	Benign	0.86
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D
PROVEAN	Uncertain	-3.1	D;.;.;D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.;.;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		0.96	.;.;.;.;.;D
Vest4		0.96
MutPred		0.77		Gain of phosphorylation at M1 (P = 0.0587);Gain of phosphorylation at M1 (P = 0.0587);Gain of phosphorylation at M1 (P = 0.0587);Gain of phosphorylation at M1 (P = 0.0587);Gain of phosphorylation at M1 (P = 0.0587);Gain of phosphorylation at M1 (P = 0.0587);
MVP		0.99
ClinPred		0.99	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: chr12-121416573;