chr12-120978923-GC-CT

Position:

• chr12-120978923-GC-CT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The c.155_156delinsCT variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of Glycine to Alanine at codon 52 (p.(Gly52Ala)) of transcript NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0024, which is greater than the MDEP threshold for BA1 (≥0.0001) (BA1). In summary, c.155_156delinsCT meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA159995/MONDO:0015967/017

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Benign reviewed by expert panel U:2 B:6 O:1
• Conservation: PhyloP100: 1.08

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 Benign. Variant got -8 ACMG points.

• BA1: 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.155_156delinsCT	p.Gly52Ala	missense_variant	1/10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.155_156delinsCT	p.Gly52Ala	missense_variant	1/10		NP_001293108.2
HNF1A	NM_001406915.1	c.155_156delinsCT	p.Gly52Ala	missense_variant	1/9		NP_001393844.1
HNF1A	XM_024449168.2	c.155_156delinsCT	p.Gly52Ala	missense_variant	1/9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.155_156delinsCT	p.Gly52Ala	missense_variant	1/10	1	NM_000545.8	ENSP00000257555	P4
HNF1A-AS1	ENST00000619441.1	n.128+1720_128+1721delinsAG		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Benign

Submissions summary: Uncertain:2 Benign:6 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Uncertain:1 Benign:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 22, 2017	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 14, 2024	Variant summary: HNF1A c.155_156delinsCT (p.Gly52Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 269658 control chromosomes. The observed variant frequency is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in HNF1A causing Maturity Onset Diabetes Of The Young 3 phenotype (2.5e-05), strongly suggesting that the variant is benign. c.155_156delinsCT has been reported in the literature in individuals affected with Maturity Onset Diabetes Of The Young 3 (Elbein_2000, Bennett_2014) without evidence for causality. 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: 10690959, 25555642). ClinVar contains an entry for this variant (Variation ID: 134503). Based on the evidence outlined above, the variant was classified as likely benign. -

Maturity onset diabetes mellitus in young Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 08, 2016	The c.155_156delGCinsCT variant (also known as p.G52A), located in coding exon 1 of the HNF1A gene, results from an in-frame deletion of GC and insertion of CT at nucleotide positions 155 to 156. This results in the substitution of the glycine residue for an alanine residue at codon 52, an amino acid with similar properties. Based on data from the Exome Aggregation Consortium (ExAC), the c.155_156delGCinsCT allele has an overall frequency of approximately 0.03% of total alleles studied, having been observed in 0.3% African alleles. In a study of African American families with type 2 diabetes, this alteration was present in two siblings with the disease as well as in their non-diabetic sibling (Elbein SC et al. Metab. Clin. Exp., 2000 Feb;49:280-4). In a study of 586 individuals with auto-antibody negative diabetes diagnosed before age 20, the p.G52A alteration (resulting from c.155G>C) was described in one individual; however, family history of diabetes was not part of the inclusion criteria and 20% of the patients positive for MODY alterations were African American (Pihoker C et al. J. Clin. Endocrinol. Metab., 2013 Oct;98:4055-62). This amino acid position is well conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Likely benign, 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. Sufficient evidence is found to confer the association of this particular variant rs587778393 with MODY3. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 15, 2020	This variant is associated with the following publications: (PMID: 10690959, 25555642, 23348805, 24728327) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	- -

Monogenic diabetes Benign:1

Benign, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

May 02, 2022

The c.155_156delinsCT variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of Glycine to Alanine at codon 52 (p.(Gly52Ala)) of transcript NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0024, which is greater than the MDEP threshold for BA1 (greater than or equal to 0.0001) (BA1). In summary, c.155_156delinsCT meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): BA1. -

HNF1A-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 28, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587778393; hg19: chr12-121416726;