12-120978551-T-C

Position:

• chr12-120978551-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000545.8(HNF1A):​c.-218T>C variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.0000114 in 615,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000086 (0 hom.)
• Consequence: HNF1A NM_000545.8 5_prime_UTR
• Clinical Significance: Uncertain significance reviewed by expert panel U:2
• Conservation: PhyloP100: 4.05

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1A	NM_000545.8	c.-218T>C		5_prime_UTR_variant	1/10	ENST00000257555.11
HNF1A	NM_001306179.2	c.-218T>C		5_prime_UTR_variant	1/10
HNF1A	NM_001406915.1	c.-218T>C		5_prime_UTR_variant	1/9
HNF1A	XM_024449168.2	c.-218T>C		5_prime_UTR_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11	c.-218T>C		5_prime_UTR_variant	1/10	1	NM_000545.8	P4
HNF1A-AS1	ENST00000619441.1	n.128+2093A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151774 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000862 AC: 4 AN: 463974 Hom.: 0 Cov.: 3 AF XY: 0.0000121 AC XY: 3 AN XY: 247354

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151774 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74102

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Aug 11, 2021

The c.-218T>C variant in the HNF1 homeobox 1 gene, HNF1A gene, is a single nucleotide variant within the promoter region of NM_000545.8. This variant is located within the overlapping HNF3 and NF-Y sites (c.-209 to c.-227) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant was identified in five unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (internal lab contributors); however, PS4 cannot be applied because the frequency of the c.-218T>C variant is 0.0000319 in gnomAD v2.1.1, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither PM2_Supporting, BS1, nor PS4_moderate can be applied. Additionally, functional studies demonstrated the variant has transactivation activity at 70% of wildtype, suggesting that this variant does not impact protein function, however sufficient controls were not used per MDEP guidelines and therefore BS3 cannot be applied (PMID: 10649494). Taken together, this evidence supports the classification of this variant as a variant of uncertain significance. ACMP/AMP criteria applied, as specified by the ClinGen MDEP VCEP: PM1_Supporting (specification version 1.0). -

HNF1A-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 27, 2024

The HNF1A c.-218T>C variant is located in the 5' untranslated region. This variant has been previously reported in one individual with maturity onset diabetes of the young (MODY) (Godart et al. 2000. PubMed ID: 10649494). An in vitro assay found that the c.-218T>C variant had a roughly 30% reduction in transcriptional activity compared to a wild-type construct (Godart et al 2000. PubMed ID: 10649494). However, no family studies were performed to help assess the pathogenicity of this variant. This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is classified as uncertain significance by ClinGen Monogenic Diabetes Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/1327603/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Benign	0.91

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: rs1024131753; hg19: chr12-121416354;