rs1169289

Variant names:

• chr12-120978819-C-G
• rs1169289
• NM_000545.8:c.51C>G

Your query was ambiguous. Multiple possible variants found:

• chr12-120978819-C-G
• chr12-120978819-C-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_000545.8(HNF1A):​c.51C>G​(p.Leu17Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 1,612,708 control chromosomes in the GnomAD database, including 168,468 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L17L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.43 (14384 hom., cov: 31)
  • Exomes 𝑓: 0.46 (154084 hom.)
• Consequence: HNF1A NM_000545.8 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 0.150
• Publications: 49 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 12-120978819-C-G is Benign according to our data. Variant chr12-120978819-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 129234.
• BP7: Synonymous conserved (PhyloP=0.15 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.551 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.51C>G	p.Leu17Leu	synonymous_variant	Exon 1 of 10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.51C>G	p.Leu17Leu	synonymous_variant	Exon 1 of 10		NP_001293108.2
HNF1A	NM_001406915.1	c.51C>G	p.Leu17Leu	synonymous_variant	Exon 1 of 9		NP_001393844.1
HNF1A	XM_024449168.2	c.51C>G	p.Leu17Leu	synonymous_variant	Exon 1 of 9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.51C>G	p.Leu17Leu	synonymous_variant	Exon 1 of 10	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes AF: 0.430 AC: 65330 AN: 151822 Hom.: 14382 Cov.: 31

Gnomad AFR AF: 0.333

Gnomad AMI AF: 0.438

Gnomad AMR AF: 0.459

Gnomad ASJ AF: 0.579

Gnomad EAS AF: 0.389

Gnomad SAS AF: 0.570

Gnomad FIN AF: 0.499

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.465

GnomAD2 exomes AF: 0.469 AC: 116345 AN: 247862 AF XY: 0.479

Gnomad AFR exome AF: 0.334

Gnomad AMR exome AF: 0.443

Gnomad ASJ exome AF: 0.582

Gnomad EAS exome AF: 0.390

Gnomad FIN exome AF: 0.491

Gnomad NFE exome AF: 0.465

Gnomad OTH exome AF: 0.485

GnomAD4 exome AF: 0.457 AC: 667007 AN: 1460768 Hom.: 154084 Cov.: 57 AF XY: 0.462 AC XY: 335487 AN XY: 726714

African (AFR) AF: 0.341 AC: 11417 AN: 33474

American (AMR) AF: 0.448 AC: 20011 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.584 AC: 15256 AN: 26122

East Asian (EAS) AF: 0.431 AC: 17112 AN: 39694

South Asian (SAS) AF: 0.571 AC: 49212 AN: 86238

European-Finnish (FIN) AF: 0.480 AC: 25276 AN: 52626

Middle Eastern (MID) AF: 0.630 AC: 3631 AN: 5766

European-Non Finnish (NFE) AF: 0.447 AC: 497178 AN: 1111782

Other (OTH) AF: 0.463 AC: 27914 AN: 60350

GnomAD4 genome AF: 0.430 AC: 65348 AN: 151940 Hom.: 14384 Cov.: 31 AF XY: 0.436 AC XY: 32371 AN XY: 74242

African (AFR) AF: 0.332 AC: 13781 AN: 41458

American (AMR) AF: 0.459 AC: 6999 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.579 AC: 2003 AN: 3462

East Asian (EAS) AF: 0.389 AC: 2003 AN: 5146

South Asian (SAS) AF: 0.569 AC: 2744 AN: 4822

European-Finnish (FIN) AF: 0.499 AC: 5270 AN: 10558

Middle Eastern (MID) AF: 0.629 AC: 185 AN: 294

European-Non Finnish (NFE) AF: 0.456 AC: 30978 AN: 67924

Other (OTH) AF: 0.469 AC: 988 AN: 2106

Alfa AF: 0.426 Hom.: 4247

Bravo AF: 0.420

Asia WGS AF: 0.495 AC: 1718 AN: 3478

EpiCase AF: 0.468

EpiControl AF: 0.468

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 22, 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.

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.

Maturity-onset diabetes of the young type 3 Benign:3

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 12, 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.

Maturity onset diabetes mellitus in young Benign:2

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Likely 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. May respond well to sulfonylureas. Sufficient evidence is found to confer the association of this particular variant rs1169289 with MODY3.

Dec 08, 2014

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.

not provided Benign:2

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

Type 2 diabetes mellitus Uncertain:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Uncertain significance

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, the role of rs1169289 of the HNF1A gene in predisposition for diabetes is not certain and needs clinical evidence.

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.13
DANN	Benign	0.58
PhyloP100		0.15
PromoterAI		0.023	Neutral
Mutation Taster		=100/0	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: rs1169289; hg19: chr12-121416622; COSMIC: COSV57459740;