rs2868094

Variant names:

• chr20-44397976-T-C
• rs2868094
• NM_175914.5:c.50-8082T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_175914.5(HNF4A):​c.50-8082T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.39 in 151,982 control chromosomes in the GnomAD database, including 12,807 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.39 (12807 hom., cov: 32)
• Consequence: HNF4A NM_175914.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.811
• Publications: 15 publications found

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]

HNF4A Gene-Disease associations (from GenCC):

• maturity-onset diabetes of the young type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• monogenic diabetes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• diabetes mellitus, noninsulin-dependent

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, G2P
• hyperinsulinism due to HNF4A deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.581 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175914.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF4A	NM_175914.5	MANE Select	c.50-8082T>C		intron	N/A	NP_787110.2
	HNF4A	NM_001287183.2		c.40+7297T>C		intron	N/A	NP_001274112.1
	HNF4A	NM_001030003.3		c.50-8082T>C		intron	N/A	NP_001025174.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF4A	ENST00000316673.9	TSL:1 MANE Select	c.50-8082T>C		intron	N/A	ENSP00000315180.4
	HNF4A	ENST00000457232.5	TSL:1	c.50-8082T>C		intron	N/A	ENSP00000396216.1
	HNF4A	ENST00000609795.5	TSL:1	c.50-8082T>C		intron	N/A	ENSP00000476609.1

Frequencies

GnomAD3 genomes AF: 0.390 AC: 59209 AN: 151864 Hom.: 12793 Cov.: 32

Gnomad AFR AF: 0.587

Gnomad AMI AF: 0.508

Gnomad AMR AF: 0.271

Gnomad ASJ AF: 0.365

Gnomad EAS AF: 0.318

Gnomad SAS AF: 0.469

Gnomad FIN AF: 0.305

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.310

Gnomad OTH AF: 0.366

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.390 AC: 59247 AN: 151982 Hom.: 12807 Cov.: 32 AF XY: 0.390 AC XY: 28973 AN XY: 74290

African (AFR) AF: 0.587 AC: 24322 AN: 41428

American (AMR) AF: 0.271 AC: 4134 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.365 AC: 1266 AN: 3472

East Asian (EAS) AF: 0.318 AC: 1648 AN: 5176

South Asian (SAS) AF: 0.468 AC: 2249 AN: 4808

European-Finnish (FIN) AF: 0.305 AC: 3216 AN: 10554

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.310 AC: 21044 AN: 67958

Other (OTH) AF: 0.364 AC: 768 AN: 2110

Alfa AF: 0.332 Hom.: 33732

Bravo AF: 0.389

Asia WGS AF: 0.383 AC: 1336 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	5.8
DANN	Benign	0.42
PhyloP100		-0.81
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2868094; hg19: chr20-43026616;