NM_000545.8:c.-187C>A

Variant names:

• chr12-120978582-C-A
• rs970766228
• NM_000545.8:c.-187C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1_Supporting PM2_Supporting PP4

This summary comes from the ClinGen Evidence Repository: The c.-187C>A variant in the HNF1 homeobox A gene, HNF1A, is a single nucleotide variant within the promoter of NM_000545.8. This variant is located within the API binding site (c.-187 to c.-195) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant has an incomputable gnomAD v4.1.0 Grpmax filtering allele frequency due to 1 copy in the European non-Finnish subpopulation and 0 copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributor). In summary, c.-187C>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0.0, approved 6/30/2025): PP4, PM1_Supporting, PM2_Supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA2480594443/MONDO:0015967/017

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000020 (0 hom.)
• Consequence: HNF1A NM_000545.8 5_prime_UTR
• Clinical Significance: Uncertain significance reviewed by expert panel U:1
• Conservation: PhyloP100: 1.21
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.-187C>A		5_prime_UTR_variant	Exon 1 of 10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.-187C>A		5_prime_UTR_variant	Exon 1 of 10		NP_001293108.2
HNF1A	NM_001406915.1	c.-187C>A		5_prime_UTR_variant	Exon 1 of 9		NP_001393844.1
HNF1A	XM_024449168.2	c.-187C>A		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	c.-187C>A		5_prime_UTR_variant	Exon 1 of 10	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000201 AC: 1 AN: 498272 Hom.: 0 Cov.: 4 AF XY: 0.00000375 AC XY: 1 AN XY: 266850

African (AFR) AF: 0.00 AC: 0 AN: 14246

American (AMR) AF: 0.00 AC: 0 AN: 28058

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16154

East Asian (EAS) AF: 0.00 AC: 0 AN: 31556

South Asian (SAS) AF: 0.00 AC: 0 AN: 52964

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30636

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2248

European-Non Finnish (NFE) AF: 0.00000340 AC: 1 AN: 294326

Other (OTH) AF: 0.00 AC: 0 AN: 28084

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Uncertain:1

Jul 24, 2025

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.-187C>A variant in the HNF1 homeobox A gene, HNF1A, is a single nucleotide variant within the promoter of NM_000545.8. This variant is located within the API binding site (c.-187 to c.-195) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant has an incomputable gnomAD v4.1.0 Grpmax filtering allele frequency due to 1 copy in the European non-Finnish subpopulation and 0 copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributor). In summary, c.-187C>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0.0, approved 6/30/2025): PP4, PM1_Supporting, PM2_Supporting). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	18
DANN	Benign	0.90
PhyloP100		1.2
PromoterAI		-0.028	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=32/268	disease causing

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: rs970766228; hg19: chr12-121416385;