rs1169289

chr12-120978819-C-Gchr12-120978819-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_000545.8(HNF1A):c.51C>G(p.Leu17=) 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:10
• Conservation: PhyloP100: 0.150

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 -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 id is 129234.We mark this variant Likely_benign, oryginal submissions are: {Benign=8, Likely_benign=1, Uncertain_significance=1}. Variant chr12-120978819-C-G is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
HNF1A	NM_000545.8	c.51C>G	p.Leu17=	synonymous_variant	1/10	ENST00000257555.11
HNF1A	NM_001306179.2	c.51C>G	p.Leu17=	synonymous_variant	1/10
HNF1A	NM_001406915.1	c.51C>G	p.Leu17=	synonymous_variant	1/9
HNF1A	XM_024449168.2	c.51C>G	p.Leu17=	synonymous_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11	c.51C>G	p.Leu17=	synonymous_variant	1/10	1	NM_000545.8	P4
HNF1A-AS1	ENST00000619441.1	n.128+1825G>C		intron_variant, non_coding_transcript_variant		3

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

GnomAD3 exomes AF: 0.469 AC: 116345 AN: 247862 Hom.: 28020 AF XY: 0.479 AC XY: 64629 AN XY: 134888

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 SAS exome AF: 0.575

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

Gnomad4 AFR exome AF: 0.341

Gnomad4 AMR exome AF: 0.448

Gnomad4 ASJ exome AF: 0.584

Gnomad4 EAS exome AF: 0.431

Gnomad4 SAS exome AF: 0.571

Gnomad4 FIN exome AF: 0.480

Gnomad4 NFE exome AF: 0.447

Gnomad4 OTH exome AF: 0.463

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

Gnomad4 AFR AF: 0.332

Gnomad4 AMR AF: 0.459

Gnomad4 ASJ AF: 0.579

Gnomad4 EAS AF: 0.389

Gnomad4 SAS AF: 0.569

Gnomad4 FIN AF: 0.499

Gnomad4 NFE AF: 0.456

Gnomad4 OTH AF: 0.469

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:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 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	-	- -

Maturity onset diabetes mellitus in young Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 08, 2014	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. -
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 rs1169289 with MODY3. -

not provided Benign:2

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

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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

Type 2 diabetes mellitus Uncertain:1

Uncertain significance, 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, 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

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
Cadd	Benign	0.13
Dann	Benign	0.58

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: rs1169289; hg19: chr12-121416622; COSMIC: COSV57459740;