rs56348580

chr12-120994314-G-Cchr12-120994314-G-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.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 NM_000545.8 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: -0.278

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]

ACMG classification

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	UniProt
HNF1A	NM_000545.8	c.864G>C	p.Gly288=	synonymous_variant	4/10	ENST00000257555.11
HNF1A	NM_001306179.2	c.864G>C	p.Gly288=	synonymous_variant	4/10
HNF1A	NM_001406915.1	c.864G>C	p.Gly288=	synonymous_variant	4/9
HNF1A	XM_024449168.2	c.864G>C	p.Gly288=	synonymous_variant	4/9

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39771 AN: 151610 Hom.: 5688 Cov.: 32

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

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.: 50 AF XY: 0.278 AC XY: 200498 AN XY: 722496

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.: 32 AF XY: 0.257 AC XY: 19025 AN XY: 74136

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:1 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:8

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

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

Invitae

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

Other links and lift over

dbSNP: rs56348580; hg19: chr12-121432117; COSMIC: COSV57459764; COSMIC: COSV57459764;