12-121001077-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1_Moderate PM2 PP5_Very_Strong

The NM_000545.8(HNF1A):c.1781G>T(p.Ser594Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,212 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S594G) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 5.13

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 12 ACMG points.

• PS1: Transcript NM_000545.8 (HNF1A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-121001077-G-T is Pathogenic according to our data. Variant chr12-121001077-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1315998.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-121001077-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1A	NM_000545.8	c.1781G>T	p.Ser594Ile	missense_variant	10/10	ENST00000257555.11
C12orf43	NM_022895.3	c.*3076C>A		3_prime_UTR_variant	6/6	ENST00000288757.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11	c.1781G>T	p.Ser594Ile	missense_variant	10/10	1	NM_000545.8	P4
C12orf43	ENST00000288757.7	c.*3076C>A		3_prime_UTR_variant	6/6	1	NM_022895.3	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461212 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726910

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 22, 2023	This variant has been identified in multiple unrelated individuals with clinical features associated with this gene and appears to segregate with disease in multiple families (personal communication related to ClinVar ID: 1315998, Accession: SCV002558822.1). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 11942313, 28012402, 9392505, 18003757, 28170077) -

Monogenic diabetes Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Jul 01, 2022

The c.1781G>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to isoleucine at codon 594 (p.(Ser594Ile)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.73, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant was identified in at least 8 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 9392505, internal lab contributors). This variant segregated with diabetes, with at least 5 informative meioses in four families with MODY (PP1_Strong; internal lab contributors). Lastly, this variant was identified in at least one individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result <50% but antibody-negative and sulfonylurea-sensitive, negative genetic testing for HNF4A) (PP4; PMID: internal lab contributors). In summary, c.1781G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 9/30/21): PP3, PM2_Supporting, PS4, PP1_Strong, PP4. -

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

Pathogenic, criteria provided, single submitter

research

Geisinger Clinic, Geisinger Health System

Aug 02, 2022

PP3, PM2, PS4, PP1_Strong, PP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Uncertain	0.72	D;D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.0	N;.;.;N;N
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;.;.;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D
Polyphen		1.0	.;.;.;.;D
Vest4		0.54
MutPred		0.65		.;.;.;.;Loss of phosphorylation at S601 (P = 0.017);
MVP		0.97
MPC		0.51
ClinPred		0.84	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: chr12-121438880; COSMIC: COSV56567261; COSMIC: COSV56567261;