20-44428840-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_175914.5(HNF4A):c.1216+353G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.409 in 151,936 control chromosomes in the GnomAD database, including 13,121 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 0.41 (13121 hom., cov: 32)
• Consequence: HNF4A NM_175914.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.628

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.63 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF4A	NM_175914.5	c.1216+353G>T		intron_variant		ENST00000316673.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF4A	ENST00000316673.9	c.1216+353G>T		intron_variant		1	NM_175914.5

Frequencies

GnomAD3 genomes AF: 0.408 AC: 62016 AN: 151818 Hom.: 13097 Cov.: 32

Gnomad AFR AF: 0.459

Gnomad AMI AF: 0.298

Gnomad AMR AF: 0.505

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.649

Gnomad SAS AF: 0.460

Gnomad FIN AF: 0.360

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.353

Gnomad OTH AF: 0.392

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

GnomAD4 genome AF: 0.409 AC: 62092 AN: 151936 Hom.: 13121 Cov.: 32 AF XY: 0.412 AC XY: 30590 AN XY: 74246

Gnomad4 AFR AF: 0.459

Gnomad4 AMR AF: 0.506

Gnomad4 ASJ AF: 0.254

Gnomad4 EAS AF: 0.649

Gnomad4 SAS AF: 0.460

Gnomad4 FIN AF: 0.360

Gnomad4 NFE AF: 0.353

Gnomad4 OTH AF: 0.392

Alfa AF: 0.350 Hom.: 10017

Bravo AF: 0.422

Asia WGS AF: 0.530 AC: 1843 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	10
Dann	Benign	0.60

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: rs3818247; hg19: chr20-43057480; COSMIC: COSV57381023; COSMIC: COSV57381023;