12-120978597-A-AGGGTTGG

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_000545.8(HNF1A):c.-160_-154dup 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
• Clinical Significance: Benign reviewed by expert panel U:2 B:4
• Conservation: PhyloP100: 4.36

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

Verdict is Benign. Variant got -12 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.
• BS2: High AC in GnomAd at 935 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1A	NM_000545.8	c.-160_-154dup		5_prime_UTR_variant	1/10	ENST00000257555.11
HNF1A	NM_001306179.2	c.-160_-154dup		5_prime_UTR_variant	1/10
HNF1A	NM_001406915.1	c.-160_-154dup		5_prime_UTR_variant	1/9
HNF1A	XM_024449168.2	c.-160_-154dup		5_prime_UTR_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11	c.-160_-154dup		5_prime_UTR_variant	1/10	1	NM_000545.8	P4
HNF1A-AS1	ENST00000619441.1	n.128+2046_128+2047insCCAACCC		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00641 AC: 935 AN: 145940 Hom.: 4 Cov.: 31

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

GnomAD3 exomes AF: 0.00470 AC: 510 AN: 108504 Hom.: 2 AF XY: 0.00413 AC XY: 242 AN XY: 58580

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 SAS exome AF: 0.000888

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.: 17 Cov.: 5 AF XY: 0.00649 AC XY: 1808 AN XY: 278692

Gnomad4 AFR exome AF: 0.00147

Gnomad4 AMR exome AF: 0.00603

Gnomad4 ASJ exome AF: 0.000285

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00156

Gnomad4 FIN exome AF: 0.0147

Gnomad4 NFE exome AF: 0.00879

Gnomad4 OTH exome AF: 0.00614

GnomAD4 genome AF: 0.00641 AC: 936 AN: 146042 Hom.: 4 Cov.: 31 AF XY: 0.00706 AC XY: 502 AN XY: 71114

Gnomad4 AFR AF: 0.00158

Gnomad4 AMR AF: 0.00862

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000208

Gnomad4 SAS AF: 0.00244

Gnomad4 FIN AF: 0.0142

Gnomad4 NFE AF: 0.00876

Gnomad4 OTH AF: 0.00645

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:2 Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 25, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 09, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 26, 2022

- -

Maturity onset diabetes mellitus in young Benign:1

Benign, 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. 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

Benign, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Apr 12, 2022

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs538476099; hg19: chr12-121416400;