rs1169288

Variant names:

• chr12-120978847-A-C
• rs1169288
• NM_000545.8:c.79A>C

Your query was ambiguous. Multiple possible variants found:

• chr12-120978847-A-C
• chr12-120978847-A-G
• chr12-120978847-A-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong 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 Likely benign (★★). 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: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:16 O:3
• Conservation: PhyloP100: 3.21
• Publications: 317 publications found

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

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 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 Benign/Likely_benign. ClinVar VariationId is 14937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.401 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000545.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1A	NM_000545.8	MANE Select	c.79A>C	p.Ile27Leu	missense	Exon 1 of 10	NP_000536.6
	HNF1A	NM_001306179.2		c.79A>C	p.Ile27Leu	missense	Exon 1 of 10	NP_001293108.2
	HNF1A	NM_001406915.1		c.79A>C	p.Ile27Leu	missense	Exon 1 of 9	NP_001393844.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1A	ENST00000257555.11	TSL:1 MANE Select	c.79A>C	p.Ile27Leu	missense	Exon 1 of 10	ENSP00000257555.5
	HNF1A	ENST00000544413.2	TSL:1	c.79A>C	p.Ile27Leu	missense	Exon 1 of 10	ENSP00000438804.1
	HNF1A	ENST00000538646.5	TSL:1	n.79A>C		non_coding_transcript_exon	Exon 1 of 6	ENSP00000443964.1

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

GnomAD2 exomes AF: 0.355 AC: 88280 AN: 248756 AF XY: 0.361

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 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

African (AFR) AF: 0.116 AC: 3874 AN: 33474

American (AMR) AF: 0.367 AC: 16383 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.469 AC: 12238 AN: 26120

East Asian (EAS) AF: 0.464 AC: 18405 AN: 39688

South Asian (SAS) AF: 0.421 AC: 36316 AN: 86240

European-Finnish (FIN) AF: 0.387 AC: 20456 AN: 52848

Middle Eastern (MID) AF: 0.489 AC: 2820 AN: 5766

European-Non Finnish (NFE) AF: 0.320 AC: 356084 AN: 1111646

Other (OTH) AF: 0.341 AC: 20605 AN: 60366

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

African (AFR) AF: 0.125 AC: 5167 AN: 41466

American (AMR) AF: 0.344 AC: 5256 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.458 AC: 1587 AN: 3466

East Asian (EAS) AF: 0.411 AC: 2114 AN: 5140

South Asian (SAS) AF: 0.416 AC: 2003 AN: 4816

European-Finnish (FIN) AF: 0.404 AC: 4272 AN: 10580

Middle Eastern (MID) AF: 0.514 AC: 151 AN: 294

European-Non Finnish (NFE) AF: 0.328 AC: 22266 AN: 67902

Other (OTH) AF: 0.317 AC: 668 AN: 2106

Alfa AF: 0.327 Hom.: 23881

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: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:16 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Maturity-onset diabetes of the young type 3 Pathogenic:1 Benign:5

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: research

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.

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 01, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:5 Other:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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.

Nov 18, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 21, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

not provided Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 12, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Type 2 diabetes mellitus Benign:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

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.

Nonpapillary renal cell carcinoma Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Maturity onset diabetes mellitus in young Benign:1

Aug 19, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Insulin resistance, susceptibility to Other:1

Jun 01, 2003

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

SERUM HDL CHOLESTEROL LEVEL, MODIFIER OF Other:1

Jun 01, 2003

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.019
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-1.2	T
PhyloP100		3.2
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.92	N
REVEL	Uncertain	0.47
Sift	Benign	0.082	T
Sift4G	Benign	0.088	T
Polyphen		0.020	B
Vest4		0.24
MPC		0.66
ClinPred		0.020	T
GERP RS		4.5
PromoterAI		-0.025	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.64
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

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