rs1169288

chr12-120978847-A-Cchr12-120978847-A-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BA1

The NM_000545.8(HNF1A):c.79A>C(p.Ile27Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,612,800 control chromosomes in the GnomAD database, including 91,048 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I27S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.29 (7186 hom., cov: 32)
  • Exomes 𝑓: 0.33 (83862 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:13 O:3
• Conservation: PhyloP100: 3.21

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 -11 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000545.8
• BP4: Computational evidence support a benign effect (MetaRNN=0.0011825562).
• BP6: Variant 12-120978847-A-C is Benign according to our data. Variant chr12-120978847-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14937.We mark this variant Likely_benign, oryginal submissions are: {Benign=12, Likely_pathogenic=1, not_provided=1}. Variant chr12-120978847-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.401 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1A	NM_000545.8	c.79A>C	p.Ile27Leu	missense_variant	1/10	ENST00000257555.11
HNF1A	NM_001306179.2	c.79A>C	p.Ile27Leu	missense_variant	1/10
HNF1A	NM_001406915.1	c.79A>C	p.Ile27Leu	missense_variant	1/9
HNF1A	XM_024449168.2	c.79A>C	p.Ile27Leu	missense_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11	c.79A>C	p.Ile27Leu	missense_variant	1/10	1	NM_000545.8	P4
HNF1A-AS1	ENST00000619441.1	n.128+1797T>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.289 AC: 43843 AN: 151834 Hom.: 7184 Cov.: 32

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.400

Gnomad AMR AF: 0.344

Gnomad ASJ AF: 0.458

Gnomad EAS AF: 0.411

Gnomad SAS AF: 0.417

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.328

Gnomad OTH AF: 0.311

GnomAD3 exomes AF: 0.355 AC: 88280 AN: 248756 Hom.: 16580 AF XY: 0.361 AC XY: 48797 AN XY: 135090

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.367

Gnomad ASJ exome AF: 0.467

Gnomad EAS exome AF: 0.415

Gnomad SAS exome AF: 0.427

Gnomad FIN exome AF: 0.399

Gnomad NFE exome AF: 0.337

Gnomad OTH exome AF: 0.361

GnomAD4 exome AF: 0.333 AC: 487181 AN: 1460848 Hom.: 83862 Cov.: 43 AF XY: 0.338 AC XY: 245420 AN XY: 726756

Gnomad4 AFR exome AF: 0.116

Gnomad4 AMR exome AF: 0.367

Gnomad4 ASJ exome AF: 0.469

Gnomad4 EAS exome AF: 0.464

Gnomad4 SAS exome AF: 0.421

Gnomad4 FIN exome AF: 0.387

Gnomad4 NFE exome AF: 0.320

Gnomad4 OTH exome AF: 0.341

GnomAD4 genome AF: 0.289 AC: 43847 AN: 151952 Hom.: 7186 Cov.: 32 AF XY: 0.298 AC XY: 22137 AN XY: 74284

Gnomad4 AFR AF: 0.125

Gnomad4 AMR AF: 0.344

Gnomad4 ASJ AF: 0.458

Gnomad4 EAS AF: 0.411

Gnomad4 SAS AF: 0.416

Gnomad4 FIN AF: 0.404

Gnomad4 NFE AF: 0.328

Gnomad4 OTH AF: 0.317

Alfa AF: 0.327 Hom.: 9956

Bravo AF: 0.274

TwinsUK AF: 0.316 AC: 1170

ALSPAC AF: 0.318 AC: 1226

ESP6500AA AF: 0.121 AC: 532

ESP6500EA AF: 0.335 AC: 2881

ExAC AF: 0.348 AC: 42182

Asia WGS AF: 0.408 AC: 1414 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Benign:13 Other:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Maturity-onset diabetes of the young type 3 Pathogenic:1 Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Likely pathogenic, 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 rs1169288 with MODY3. This variant is found to be a potent moderate impact variant with a CADD score of 22.4 and sufficient scientific evidence to support the reported classification. Though this is seen to be a tolerated variant as per other insilico scores, this is reported more frequently in MODY cases as per recent evidence. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Benign:4 Other:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 18, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 21, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Type 2 diabetes mellitus Benign:1

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 and response to sulfonylureas.However, evidence shows association of rs1169288 with T2DM and further clinical validation is required in MODY cases. -

Maturity onset diabetes mellitus in young Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 19, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Nonpapillary renal cell carcinoma Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Insulin resistance, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jun 01, 2003

- -

SERUM HDL CHOLESTEROL LEVEL, MODIFIER OF Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jun 01, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Uncertain	0.020
CADD	Benign	21
DANN	Uncertain	0.98
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.019
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.55	T;T;T;T;T;T
MetaRNN	Benign	0.0012	T;T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	0.0043	P;P;P;P;P
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.92	N;.;.;.;N;N
REVEL	Uncertain	0.47
Sift	Benign	0.082	T;.;.;.;T;T
Sift4G	Benign	0.088	T;T;T;T;T;T
Polyphen		0.020	.;.;.;.;.;B
Vest4		0.24
MPC		0.66
ClinPred		0.020	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.64

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: rs1169288; hg19: chr12-121416650; COSMIC: COSV57459307;