12-120994277-C-G

Position:

• chr12-120994277-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM5_Supporting PP4_Moderate PP3 PM2_Supporting PM1_Supporting PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.827C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to glycine at codon 276 (p.(Ala276Gly)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant also is predicted to be deleterious by computational evidence, with a REVEL score of 0.901, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Additionally, this variant has a minor allele frequency of 0.000007816 in the gnomAD v2.1.1 European non-Finnish population and one copy in another subpopulation, which is less than the ClinGen MDEP threshold for PM2_Supporting (≤0.00002 and ≤1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in 6 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). At least one of these individuals had a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, antibody negative, and response to low dose sulfonylureas) (PP4_Moderate; internal lab contributor). Another missense variant, c.827C>A (p.Ala276Asp), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Ala276Gly (PM5_Supporting). In summary, c.827C>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM1_Supporting, PP3, PM2_Supporting, PS4_Moderate, PP4_Moderate, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA214333/MONDO:0015967/017

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6 U:1
• Conservation: PhyloP100: 7.49

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: 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	c.827C>G	p.Ala276Gly	missense_variant	4/10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.827C>G	p.Ala276Gly	missense_variant	4/10		NP_001293108.2
HNF1A	NM_001406915.1	c.827C>G	p.Ala276Gly	missense_variant	4/9		NP_001393844.1
HNF1A	XM_024449168.2	c.827C>G	p.Ala276Gly	missense_variant	4/9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.827C>G	p.Ala276Gly	missense_variant	4/10	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248546 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134644

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: 0.00000958 AC: 14 AN: 1461078 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 726786

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 05, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 15, 2025	Reported in association with MODY in published literature (PMID: 18003757, 22432796); detailed patient clinical information not provided; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24097065, 27899486, 22432796, 33363396, 36208030, 18003757, 12453420) -

Maturity-onset diabetes of the young type 3 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 06, 2023	- -

Monogenic diabetes Pathogenic:1 Uncertain:1

Likely pathogenic, reviewed by expert panel	curation	ClinGen Monogenic Diabetes Variant Curation Expert Panel	May 03, 2022	The c.827C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to glycine at codon 276 (p.(Ala276Gly)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant also is predicted to be deleterious by computational evidence, with a REVEL score of 0.901, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Additionally, this variant has a minor allele frequency of 0.000007816 in the gnomAD v2.1.1 European non-Finnish population and one copy in another subpopulation, which is less than the ClinGen MDEP threshold for PM2_Supporting (less than or equal to 0.00002 and less than or equal to 1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in 6 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). At least one of these individuals had a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, antibody negative, and response to low dose sulfonylureas) (PP4_Moderate; internal lab contributor). Another missense variant, c.827C>A (p.Ala276Asp), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Ala276Gly (PM5_Supporting). In summary, c.827C>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM1_Supporting, PP3, PM2_Supporting, PS4_Moderate, PP4_Moderate, PM5_Supporting. -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Ala276Gly variant in HNF1A has been reported in 2 individuals with Monogenic Diabetes (PMID: 18003757, 22432796), and has been identified in 0.004101% (1/24384) of African chromosomes and 0.0007816% (1/127936) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs137853245). This variant has also been reported in 1 individual without diabetes (PMID: 24097065). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic in ClinVar (Variation ID: 36832). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional variant causing a different amino acid change at the same position, p.Ala276Asp, has been reported in association with disease in ClinVar, slightly supporting that a change at this position may not be tolerated (Variation ID: 14945). Multiple variants in the same region as p.Ala276Gly have been reported in association with disease in ClinVar, suggesting that this variant is in a mutational hot spot and slightly supports pathogenicity (Variation ID: 447504, 14931, 447503, 449403, 265193). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3, PM5_Supporting, PS4_Supporting, PM1_Supporting (Richards 2015). -

Diabetes mellitus type 1;C0011860:Type 2 diabetes mellitus;C1838100:Maturity-onset diabetes of the young type 3;C1840646:Hepatic adenomas, familial;C2675866:Type 1 diabetes mellitus 20;CN074294:Nonpapillary renal cell carcinoma Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 06, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	.;T;T;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Pathogenic	0.99	D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.3	N;.;N;N
REVEL	Pathogenic	0.90
Sift	Benign	0.034	D;.;D;D
Sift4G	Uncertain	0.0060	D;D;D;D
Polyphen		0.97	.;.;.;D
Vest4		0.85
MVP		0.98
MPC		0.40
ClinPred		0.97	D
GERP RS		4.8
gMVP		0.95

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

LitVar

Other links and lift over

dbSNP: rs137853245; hg19: chr12-121432080; COSMIC: COSV57463922; COSMIC: COSV57463922;