12-120978597-A-AGGGTTGG

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_000545.8(HNF1A):c.-160_-154dupTGGGGGT variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.00685 in 664,898 control chromosomes in the GnomAD database, including 21 homozygotes. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.0064 ( 4 hom., cov: 31)

Exomes 𝑓: 0.0070 ( 17 hom. )

Consequence

HNF1A
NM_000545.8 5_prime_UTR

Scores

Not classified

Clinical Significance

Benign reviewed by expert panel U:2B:5

Conservation

PhyloP100: 4.36

Publications

1 publications found

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 was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 12-120978597-A-AGGGTTGG is Benign according to our data. Variant chr12-120978597-A-AGGGTTGG is described in ClinVar as [Benign]. Clinvar id is 288582.Status of the report is reviewed_by_expert_panel, 3 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00641 (936/146042) while in subpopulation NFE AF = 0.00876 (581/66296). AF 95% confidence interval is 0.00817. There are 4 homozygotes in GnomAd4. There are 502 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 936 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8 link	c.-160_-154dupTGGGGGT	5_prime_UTR_variant	Exon 1 of 10	ENST00000257555.11	NP_000536.6	P20823E0YMI7
HNF1A	NM_001306179.2 link	c.-160_-154dupTGGGGGT	5_prime_UTR_variant	Exon 1 of 10		NP_001293108.2	P20823E0YMI7
HNF1A	NM_001406915.1 link	c.-160_-154dupTGGGGGT	5_prime_UTR_variant	Exon 1 of 9		NP_001393844.1
HNF1A	XM_024449168.2 link	c.-160_-154dupTGGGGGT	5_prime_UTR_variant	Exon 1 of 9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11 link	c.-160_-154dupTGGGGGT		5_prime_UTR_variant	Exon 1 of 10	1	NM_000545.8	ENSP00000257555.5		A0A0A0MQU7

Frequencies

GnomAD3 genomes

AF:

0.00641

AC:

935

AN:

145940

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00159

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00864

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000208

Gnomad SAS

AF:

0.00221

Gnomad FIN

AF:

0.0142

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00876

Gnomad OTH

AF:

0.00652

GnomAD2 exomes

AF:

0.00470

AC:

510

AN:

108504

AF XY:

0.00413

show subpopulations

Gnomad AFR exome

AF:

0.000967

Gnomad AMR exome

AF:

0.00633

Gnomad ASJ exome

AF:

0.000357

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0134

Gnomad NFE exome

AF:

0.00703

Gnomad OTH exome

AF:

0.00379

GnomAD4 exome

AF:

0.00697

AC:

3618

AN:

518856

Hom.:

Cov.:

AF XY:

0.00649

AC XY:

1808

AN XY:

278692

show subpopulations

African (AFR)

AF:

0.00147

AC:

AN:

14974

American (AMR)

AF:

0.00603

AC:

189

AN:

31322

Ashkenazi Jewish (ASJ)

AF:

0.000285

AC:

AN:

17514

East Asian (EAS)

AF:

0.00

AC:

AN:

31280

South Asian (SAS)

AF:

0.00156

AC:

AN:

56524

European-Finnish (FIN)

AF:

0.0147

AC:

460

AN:

31328

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2402

European-Non Finnish (NFE)

AF:

0.00879

AC:

2677

AN:

304692

Other (OTH)

AF:

0.00614

AC:

177

AN:

28820

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

163

326

489

652

815

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00641

AC:

936

AN:

146042

Hom.:

Cov.:

AF XY:

0.00706

AC XY:

502

AN XY:

71114

show subpopulations

African (AFR)

AF:

0.00158

AC:

AN:

39184

American (AMR)

AF:

0.00862

AC:

128

AN:

14844

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3428

East Asian (EAS)

AF:

0.000208

AC:

AN:

4800

South Asian (SAS)

AF:

0.00244

AC:

AN:

4510

European-Finnish (FIN)

AF:

0.0142

AC:

140

AN:

9826

Middle Eastern (MID)

AF:

0.00

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.00876

AC:

581

AN:

66296

Other (OTH)

AF:

0.00645

AC:

AN:

2016

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

122

162

203

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00336

Hom.:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:2Benign:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 09, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 25, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

HNF1A: BS1, BS2 -

Diabetes mellitus type 1;C0011860:Type 2 diabetes mellitus;C1838100:Maturity-onset diabetes of the young type 3;C1840646:Hepatic adenomas, familial;C2675866:Type 1 diabetes mellitus 20;CN074294:Nonpapillary renal cell carcinoma

Benign:1

Apr 26, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Maturity onset diabetes mellitus in young

Benign:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Benign

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. Associated with glucosuria. May respond well to sulfonylureas. However, more evidence is required to confer the association of this particular variant rs538476099 with MODY3. -

Monogenic diabetes

Benign:1

Apr 12, 2022

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The c.-160_-154dup variant in the HNF1 homeobox A gene, HNF1A, is located in the promoter of NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.013, which is greater thanthe MDEP threshold for BA1 (greater than or equal to 0.0001) (BA1). Additionally, this variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributors). In summary, c.-160_-154dup meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): BA1, BP5. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.4

Mutation Taster

=296/4

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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12-120978597-A-AGGGTTGG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over