12-120978819-C-G

Position:

chr12-120978819-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BA1

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).

Frequency

Genomes: 𝑓 0.43 ( 14384 hom., cov: 31)

Exomes 𝑓: 0.46 ( 154084 hom. )

Consequence

HNF1A
NM_000545.8 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 0.150

Variant links:

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 links:

HNF1A-AS1 (HGNC:26785): (HNF1A antisense RNA 1)

HNF1A-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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: {Likely_benign=1, Benign=8, 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	Protein
HNF1A	NM_000545.8 linkuse as main transcript	c.51C>G	p.Leu17=	synonymous_variant	1/10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2 linkuse as main transcript	c.51C>G	p.Leu17=	synonymous_variant	1/10		NP_001293108.2
HNF1A	NM_001406915.1 linkuse as main transcript	c.51C>G	p.Leu17=	synonymous_variant	1/9		NP_001393844.1
HNF1A	XM_024449168.2 linkuse as main transcript	c.51C>G	p.Leu17=	synonymous_variant	1/9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11 linkuse as main transcript	c.51C>G	p.Leu17=	synonymous_variant	1/10	1	NM_000545.8	ENSP00000257555	P4
HNF1A-AS1	ENST00000619441.1 linkuse as main transcript	n.128+1825G>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.430

AC:

65330

AN:

151822

Hom.:

14382

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.462

AC XY:

335487

AN XY:

726714

show subpopulations

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.:

AF XY:

0.436

AC XY:

32371

AN XY:

74242

show subpopulations

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:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

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

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. -
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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over