12-121001077-G-T

Position:

chr12-121001077-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP1_StrongPP3PP4PM2_SupportingPS4

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA386940977/MONDO:0015967/017

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

HNF1A
NM_000545.8 missense

Scores

7

9

2

Clinical Significance

Pathogenic reviewed by expert panel P:4U:1

Conservation

PhyloP100: 5.13

Variant links:

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 links:

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]

C12orf43 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNF1A	NM_000545.8 linkuse as main transcript	c.1781G>T	p.Ser594Ile	missense_variant	10/10	ENST00000257555.11	NP_000536.6	P20823E0YMI7
C12orf43	NM_022895.3 linkuse as main transcript	c.*3076C>A		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 linkuse as main transcript	c.1781G>T	p.Ser594Ile	missense_variant	10/10	1	NM_000545.8	ENSP00000257555.5		A0A0A0MQU7
C12orf43	ENST00000288757.7 linkuse as main transcript	c.*3076C>A		3_prime_UTR_variant	6/6	1	NM_022895.3	ENSP00000288757.5		Q96C57

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

show subpopulations

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:4Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain: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) -

Maturity onset diabetes mellitus in young

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

May 21, 2024

Variant summary: HNF1A c.1781G>T (p.Ser594Ile) results in a non-conservative amino acid change located in the Hepatocyte nuclear factor 1, alpha isoform C-terminal domain (IPR006898) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250012 control chromosomes (gnomAD). c.1781G>T has been reported in the literature in individuals affected with Maturity Onset Diabetes Of The Young 3 (e.g. Boutin_1997, Ziemssen_2002, Santana_2017, Mirshahi_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 11942313, 10333057, 9392505, 28170077, 35472491, 36257325). ClinVar contains an entry for this variant (Variation ID: 1315998). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

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

DEOGEN2

Uncertain

0.61

.;D;.;T;.

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

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;