12-120979061-C-T

Variant names:

• chr12-120979061-C-T
• rs1800574
• NM_000545.8:c.293C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000545.8(HNF1A):​c.293C>T​(p.Ala98Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0292 in 1,611,476 control chromosomes in the GnomAD database, including 921 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A98T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.022 (52 hom., cov: 32)
  • Exomes 𝑓: 0.030 (869 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16 O:1
• Conservation: PhyloP100: 7.35
• Publications: 107 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-AS1 (HGNC:26785): (HNF1A antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042442083).
• BP6: Variant 12-120979061-C-T is Benign according to our data. Variant chr12-120979061-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129233.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0591 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.293C>T	p.Ala98Val	missense_variant	Exon 1 of 10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.293C>T	p.Ala98Val	missense_variant	Exon 1 of 10		NP_001293108.2
HNF1A	NM_001406915.1	c.293C>T	p.Ala98Val	missense_variant	Exon 1 of 9		NP_001393844.1
HNF1A	XM_024449168.2	c.293C>T	p.Ala98Val	missense_variant	Exon 1 of 9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.293C>T	p.Ala98Val	missense_variant	Exon 1 of 10	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes AF: 0.0220 AC: 3342 AN: 152192 Hom.: 52 Cov.: 32

Gnomad AFR AF: 0.00543

Gnomad AMI AF: 0.0253

Gnomad AMR AF: 0.0135

Gnomad ASJ AF: 0.0320

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0656

Gnomad FIN AF: 0.0475

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0278

Gnomad OTH AF: 0.0234

GnomAD2 exomes AF: 0.0290 AC: 6974 AN: 240478 AF XY: 0.0322

Gnomad AFR exome AF: 0.00543

Gnomad AMR exome AF: 0.0115

Gnomad ASJ exome AF: 0.0361

Gnomad EAS exome AF: 0.0000551

Gnomad FIN exome AF: 0.0416

Gnomad NFE exome AF: 0.0295

Gnomad OTH exome AF: 0.0277

GnomAD4 exome AF: 0.0300 AC: 43743 AN: 1459166 Hom.: 869 Cov.: 35 AF XY: 0.0313 AC XY: 22689 AN XY: 725618

African (AFR) AF: 0.00487 AC: 163 AN: 33446

American (AMR) AF: 0.0121 AC: 537 AN: 44424

Ashkenazi Jewish (ASJ) AF: 0.0348 AC: 906 AN: 26046

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39646

South Asian (SAS) AF: 0.0670 AC: 5742 AN: 85692

European-Finnish (FIN) AF: 0.0427 AC: 2258 AN: 52940

Middle Eastern (MID) AF: 0.0428 AC: 246 AN: 5742

European-Non Finnish (NFE) AF: 0.0290 AC: 32228 AN: 1110948

Other (OTH) AF: 0.0275 AC: 1659 AN: 60282

GnomAD4 genome AF: 0.0219 AC: 3337 AN: 152310 Hom.: 52 Cov.: 32 AF XY: 0.0232 AC XY: 1725 AN XY: 74484

African (AFR) AF: 0.00544 AC: 226 AN: 41576

American (AMR) AF: 0.0134 AC: 205 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0320 AC: 111 AN: 3470

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5186

South Asian (SAS) AF: 0.0650 AC: 314 AN: 4830

European-Finnish (FIN) AF: 0.0475 AC: 504 AN: 10618

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0278 AC: 1893 AN: 68016

Other (OTH) AF: 0.0227 AC: 48 AN: 2114

Alfa AF: 0.0268 Hom.: 185

Bravo AF: 0.0181

TwinsUK AF: 0.0275 AC: 102

ALSPAC AF: 0.0270 AC: 104

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.0257 AC: 220

ExAC AF: 0.0288 AC: 3492

Asia WGS AF: 0.0240 AC: 84 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6 Other:1

Mar 04, 2013

Genetic Services Laboratory, University of Chicago

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

- -

Apr 26, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 19, 2014

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. -

not provided Benign:3

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 31, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Maturity onset diabetes mellitus in young Benign:2

Sep 18, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Mutations in this gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. Good response to sulfonylureas. However, rs1800574 localized in the DNA-binding domain of the HNF1A gene (p.Ala98Val) doesn't directly predispose to early-onset Diabetes Mellitus even if the prevalence of the variant is high. -

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

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ovarian cancer Benign:1

Jan 01, 2022

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Monogenic diabetes Benign:1

Feb 01, 2019

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

ACMG criteria: BA1 (overall MAF in gnomAD 3%, 6.6% in South Asian in gnomAD, ~3% in other subpop), BS2 (346 cases and 404 controls in T2DM ) [Revel score 0.597, PP3 (6), BP4 (4)= conflicting evidence, not using] [not using BP6]: benign -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	.;D;T;D;T;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D
MetaRNN	Benign	0.0042	T;T;T;T;T;T
MetaSVM	Uncertain	0.40	D
PhyloP100		7.3
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.2	N;.;.;.;N;N
REVEL	Uncertain	0.60
Sift	Benign	0.063	T;.;.;.;T;T
Sift4G	Benign	0.090	T;T;T;T;T;T
Polyphen		0.21	.;.;.;.;.;B
Vest4		0.46
MPC		0.27
ClinPred		0.086	T
GERP RS		4.5
PromoterAI		-0.020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
gMVP		0.90
Mutation Taster		=70/30	polymorphism (auto)

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: rs1800574; hg19: chr12-121416864;