12-120994314-G-C

Position:

chr12-120994314-G-C

Variant summary

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

The ENST00000257555.11(HNF1A):c.864G>C(p.Gly288=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.282 in 1,605,008 control chromosomes in the GnomAD database, including 67,823 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. G288G?) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.26 ( 5699 hom., cov: 32)

Exomes 𝑓: 0.28 ( 62124 hom. )

Consequence

HNF1A
ENST00000257555.11 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:12

Conservation

PhyloP100: -0.278

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:

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=-0.55).

BP6

Variant 12-120994314-G-C is Benign according to our data. Variant chr12-120994314-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 129236.We mark this variant Likely_benign, oryginal submissions are: {Benign=9, Uncertain_significance=1}. Variant chr12-120994314-G-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.278 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.359 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.864G>C	p.Gly288=	synonymous_variant	4/10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2 linkuse as main transcript	c.864G>C	p.Gly288=	synonymous_variant	4/10		NP_001293108.2
HNF1A	NM_001406915.1 linkuse as main transcript	c.864G>C	p.Gly288=	synonymous_variant	4/9		NP_001393844.1
HNF1A	XM_024449168.2 linkuse as main transcript	c.864G>C	p.Gly288=	synonymous_variant	4/9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11 linkuse as main transcript	c.864G>C	p.Gly288=	synonymous_variant	4/10	1	NM_000545.8	ENSP00000257555	P4

Frequencies

GnomAD3 genomes

AF:

0.262

AC:

39771

AN:

151610

Hom.:

5688

Cov.:

show subpopulations

Gnomad AFR

AF:

0.206

Gnomad AMI

AF:

0.230

Gnomad AMR

AF:

0.366

Gnomad ASJ

AF:

0.311

Gnomad EAS

AF:

0.00348

Gnomad SAS

AF:

0.0998

Gnomad FIN

AF:

0.266

Gnomad MID

AF:

0.288

Gnomad NFE

AF:

0.301

Gnomad OTH

AF:

0.283

GnomAD3 exomes

AF:

0.265

AC:

60579

AN:

228182

Hom.:

9100

AF XY:

0.255

AC XY:

31605

AN XY:

123872

show subpopulations

Gnomad AFR exome

AF:

0.198

Gnomad AMR exome

AF:

0.442

Gnomad ASJ exome

AF:

0.317

Gnomad EAS exome

AF:

0.00153

Gnomad SAS exome

AF:

0.0975

Gnomad FIN exome

AF:

0.272

Gnomad NFE exome

AF:

0.303

Gnomad OTH exome

AF:

0.286

GnomAD4 exome

AF:

0.284

AC:

412146

AN:

1453280

Hom.:

62124

Cov.:

AF XY:

0.278

AC XY:

200498

AN XY:

722496

show subpopulations

Gnomad4 AFR exome

AF:

0.203

Gnomad4 AMR exome

AF:

0.425

Gnomad4 ASJ exome

AF:

0.312

Gnomad4 EAS exome

AF:

0.00114

Gnomad4 SAS exome

AF:

0.103

Gnomad4 FIN exome

AF:

0.275

Gnomad4 NFE exome

AF:

0.305

Gnomad4 OTH exome

AF:

0.270

GnomAD4 genome

AF:

0.262

AC:

39812

AN:

151728

Hom.:

5699

Cov.:

AF XY:

0.257

AC XY:

19025

AN XY:

74136

show subpopulations

Gnomad4 AFR

AF:

0.207

Gnomad4 AMR

AF:

0.367

Gnomad4 ASJ

AF:

0.311

Gnomad4 EAS

AF:

0.00349

Gnomad4 SAS

AF:

0.101

Gnomad4 FIN

AF:

0.266

Gnomad4 NFE

AF:

0.301

Gnomad4 OTH

AF:

0.279

Alfa

AF:

0.260

Hom.:

1733

Bravo

AF:

0.273

Asia WGS

AF:

0.0810

AC:

289

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:8

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 07, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 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. -

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. HNF1A gene is associated with glucosuria and response to sulfonylureas. However, the role of rs56348580 in the predisposition to diabetes remains unclear. -

Maturity onset diabetes mellitus in young

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 13, 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

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Maturity-onset diabetes of the young type 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

5.9

DANN

Benign

0.90

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