20-44397144-T-C

Variant names:

• chr20-44397144-T-C
• rs717247
• NM_175914.5:c.50-8914T>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.50-8914T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.38 in 151,968 control chromosomes in the GnomAD database, including 11,966 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 0.38 (11966 hom., cov: 32)
• Consequence: HNF4A NM_175914.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.768
• 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=-0.78).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.547 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF4A	NM_175914.5	c.50-8914T>C		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.50-8914T>C		intron_variant	Intron 1 of 9	1	NM_175914.5	ENSP00000315180.4
HNF4A	ENST00000457232.5	c.50-8914T>C		intron_variant	Intron 1 of 9	1		ENSP00000396216.1
HNF4A	ENST00000609795.5	c.50-8914T>C		intron_variant	Intron 1 of 7	1		ENSP00000476609.1
HNF4A	ENST00000609262.5	c.40+6465T>C		intron_variant	Intron 2 of 3	1		ENSP00000476310.1

Frequencies

GnomAD3 genomes AF: 0.380 AC: 57761 AN: 151850 Hom.: 11954 Cov.: 32

Gnomad AFR AF: 0.553

Gnomad AMI AF: 0.510

Gnomad AMR AF: 0.267

Gnomad ASJ AF: 0.365

Gnomad EAS AF: 0.318

Gnomad SAS AF: 0.473

Gnomad FIN AF: 0.305

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.310

Gnomad OTH AF: 0.360

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

GnomAD4 genome AF: 0.380 AC: 57795 AN: 151968 Hom.: 11966 Cov.: 32 AF XY: 0.381 AC XY: 28266 AN XY: 74282

African (AFR) AF: 0.553 AC: 22910 AN: 41420

American (AMR) AF: 0.267 AC: 4076 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.365 AC: 1265 AN: 3466

East Asian (EAS) AF: 0.318 AC: 1642 AN: 5164

South Asian (SAS) AF: 0.471 AC: 2274 AN: 4824

European-Finnish (FIN) AF: 0.305 AC: 3224 AN: 10558

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

European-Non Finnish (NFE) AF: 0.310 AC: 21044 AN: 67942

Other (OTH) AF: 0.358 AC: 756 AN: 2112

Alfa AF: 0.350 Hom.: 1309

Bravo AF: 0.377

Asia WGS AF: 0.385 AC: 1343 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	12
DANN	Benign	0.80
PhyloP100		0.77
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: rs717247; hg19: chr20-43025784;