20-44397989-C-T

Variant names:

• chr20-44397989-C-T
• rs2425638
• NM_175914.5:c.50-8069C>T

Variant summary

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

The NM_175914.5(HNF4A):​c.50-8069C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.852 in 152,080 control chromosomes in the GnomAD database, including 55,327 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 0.85 (55327 hom., cov: 32)
• Consequence: HNF4A NM_175914.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.58
• Publications: 5 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=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.902 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF4A	NM_175914.5	c.50-8069C>T		intron_variant	Intron 1 of 9	ENST00000316673.9	NP_787110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF4A	ENST00000316673.9	c.50-8069C>T		intron_variant	Intron 1 of 9	1	NM_175914.5	ENSP00000315180.4
HNF4A	ENST00000457232.5	c.50-8069C>T		intron_variant	Intron 1 of 9	1		ENSP00000396216.1
HNF4A	ENST00000609795.5	c.50-8069C>T		intron_variant	Intron 1 of 7	1		ENSP00000476609.1
HNF4A	ENST00000609262.5	c.40+7310C>T		intron_variant	Intron 2 of 3	1		ENSP00000476310.1

Frequencies

GnomAD3 genomes AF: 0.852 AC: 129500 AN: 151962 Hom.: 55287 Cov.: 32

Gnomad AFR AF: 0.910

Gnomad AMI AF: 0.901

Gnomad AMR AF: 0.861

Gnomad ASJ AF: 0.801

Gnomad EAS AF: 0.813

Gnomad SAS AF: 0.849

Gnomad FIN AF: 0.811

Gnomad MID AF: 0.921

Gnomad NFE AF: 0.826

Gnomad OTH AF: 0.854

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

GnomAD4 genome AF: 0.852 AC: 129592 AN: 152080 Hom.: 55327 Cov.: 32 AF XY: 0.853 AC XY: 63400 AN XY: 74328

African (AFR) AF: 0.910 AC: 37752 AN: 41478

American (AMR) AF: 0.861 AC: 13166 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.801 AC: 2776 AN: 3466

East Asian (EAS) AF: 0.814 AC: 4215 AN: 5180

South Asian (SAS) AF: 0.847 AC: 4083 AN: 4820

European-Finnish (FIN) AF: 0.811 AC: 8568 AN: 10566

Middle Eastern (MID) AF: 0.918 AC: 270 AN: 294

European-Non Finnish (NFE) AF: 0.826 AC: 56138 AN: 67970

Other (OTH) AF: 0.855 AC: 1806 AN: 2112

Alfa AF: 0.837 Hom.: 73873

Bravo AF: 0.855

Asia WGS AF: 0.842 AC: 2929 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.66
DANN	Benign	0.33
PhyloP100		-4.6
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: rs2425638; hg19: chr20-43026629;