12-120994314-G-C

Variant names:

• chr12-120994314-G-C
• rs56348580
• NM_000545.8:c.864G>C

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.864G>C​(p.Gly288Gly) 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 benign.

• 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:13
• Conservation: PhyloP100: -0.278
• Publications: 53 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 Gene-Disease associations (from GenCC):

• monogenic diabetes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• type 1 diabetes mellitus 20

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp
• diabetes mellitus, noninsulin-dependent

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• maturity-onset diabetes of the young type 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• hyperinsulinism due to HNF1A deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• nonpapillary renal cell carcinoma

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 129236.
• 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 rank	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.864G>C	p.Gly288Gly	synonymous_variant	Exon 4 of 10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.864G>C	p.Gly288Gly	synonymous_variant	Exon 4 of 10		NP_001293108.2
HNF1A	NM_001406915.1	c.864G>C	p.Gly288Gly	synonymous_variant	Exon 4 of 9		NP_001393844.1
HNF1A	XM_024449168.2	c.864G>C	p.Gly288Gly	synonymous_variant	Exon 4 of 9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.864G>C	p.Gly288Gly	synonymous_variant	Exon 4 of 10	1	NM_000545.8	ENSP00000257555.5

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

GnomAD2 exomes AF: 0.265 AC: 60579 AN: 228182 AF XY: 0.255

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 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

African (AFR) AF: 0.203 AC: 6772 AN: 33372

American (AMR) AF: 0.425 AC: 18305 AN: 43028

Ashkenazi Jewish (ASJ) AF: 0.312 AC: 8059 AN: 25840

East Asian (EAS) AF: 0.00114 AC: 45 AN: 39592

South Asian (SAS) AF: 0.103 AC: 8833 AN: 85550

European-Finnish (FIN) AF: 0.275 AC: 14408 AN: 52480

Middle Eastern (MID) AF: 0.241 AC: 1389 AN: 5756

European-Non Finnish (NFE) AF: 0.305 AC: 338146 AN: 1107614

Other (OTH) AF: 0.270 AC: 16189 AN: 60048

GnomAD4 genome AF: 0.262 AC: 39812 AN: 151728 Hom.: 5699 Cov.: 32 AF XY: 0.257 AC XY: 19025 AN XY: 74136

African (AFR) AF: 0.207 AC: 8538 AN: 41340

American (AMR) AF: 0.367 AC: 5600 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 1079 AN: 3468

East Asian (EAS) AF: 0.00349 AC: 18 AN: 5164

South Asian (SAS) AF: 0.101 AC: 481 AN: 4784

European-Finnish (FIN) AF: 0.266 AC: 2801 AN: 10548

Middle Eastern (MID) AF: 0.283 AC: 82 AN: 290

European-Non Finnish (NFE) AF: 0.301 AC: 20416 AN: 67860

Other (OTH) AF: 0.279 AC: 588 AN: 2106

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:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:8

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 12, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 07, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 19, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 19, 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.

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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

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

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

Maturity onset diabetes mellitus in young Benign:1

Mar 13, 2015

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:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_noAF	Benign	-0.55
CADD	Benign	5.9
DANN	Benign	0.90
PhyloP100		-0.28
Mutation Taster		=69/31	polymorphism

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