rs751211080

Positions:

• chr20-44418530-C-A
• chr20-44418530-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PM2_Supporting BP4

This summary comes from the ClinGen Evidence Repository: The c.670+18C>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, is a single nucleotide variant within intron 6 of NM_175914.5. This variant is absent in gnomAD v2.1.1 (PM2_Supporting). However, the computational splicing predictor SpliceAI gives a score of 0.00 for donor loss, suggesting that this variant has no impact on splicing (BP4). In summary, c.670+18C>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 (specification version 2.0.0, approved 10/11/2023): PM2_Supporting, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10587354/MONDO:0015967/085

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: HNF4A ENST00000316673.9 intron
• Clinical Significance: Uncertain significance reviewed by expert panel U:1 B:2
• Conservation: PhyloP100: 0.442

Genes affected

HNF4A (HGNC:5024): (hepatocyte nuclear factor 4 alpha) The protein encoded by this gene is a nuclear transcription factor which binds DNA as a homodimer. The encoded protein controls the expression of several genes, including hepatocyte nuclear factor 1 alpha, a transcription factor which regulates the expression of several hepatic genes. This gene may play a role in development of the liver, kidney, and intestines. Mutations in this gene have been associated with monogenic autosomal dominant non-insulin-dependent diabetes mellitus type I. Alternative splicing of this gene results in multiple transcript variants encoding several different isoforms. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNF4A	NM_175914.5	c.670+18C>A		intron_variant		ENST00000316673.9	NP_787110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF4A	ENST00000316673.9	c.670+18C>A		intron_variant		1	NM_175914.5	ENSP00000315180

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000132 AC: 19 AN: 1440270 Hom.: 0 Cov.: 27 AF XY: 0.0000139 AC XY: 10 AN XY: 717890

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: 0.0000173

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Benign: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 01, 2024

The c.670+18C>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, is a single nucleotide variant within intron 6 of NM_175914.5. This variant is absent in gnomAD v2.1.1 (PM2_Supporting). However, the computational splicing predictor SpliceAI gives a score of 0.00 for donor loss, suggesting that this variant has no impact on splicing (BP4). In summary, c.670+18C>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 (specification version 2.0.0, approved 10/11/2023): PM2_Supporting, BP4. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Maturity onset diabetes mellitus in young Benign:1

Benign, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Potent mutations in HNF4A are associated with poor insulin secretion in response to hyperglycemia. Associated with MODY1. Patients initially respond well to sulfonylureas but eventually become insulin dependent. However, more evidence is required to ascertain the role of this particular variant rs751211080 in MODY, yet. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	12
DANN	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

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: rs751211080; hg19: chr20-43047170;