20-44424948-A-T

Variant names:

• chr20-44424948-A-T
• rs6073435
• NM_175914.5:c.1063+694A>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.1063+694A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.529 in 152,032 control chromosomes in the GnomAD database, including 22,067 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 0.53 (22067 hom., cov: 32)
• Consequence: HNF4A NM_175914.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.224
• Publications: 6 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=-0.74).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.6 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF4A	NM_175914.5	c.1063+694A>T		intron_variant	Intron 8 of 9	ENST00000316673.9	NP_787110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF4A	ENST00000316673.9	c.1063+694A>T		intron_variant	Intron 8 of 9	1	NM_175914.5	ENSP00000315180.4

Frequencies

GnomAD3 genomes AF: 0.529 AC: 80334 AN: 151914 Hom.: 22064 Cov.: 32

Gnomad AFR AF: 0.404

Gnomad AMI AF: 0.613

Gnomad AMR AF: 0.489

Gnomad ASJ AF: 0.707

Gnomad EAS AF: 0.332

Gnomad SAS AF: 0.570

Gnomad FIN AF: 0.583

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.605

Gnomad OTH AF: 0.562

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

GnomAD4 genome AF: 0.529 AC: 80372 AN: 152032 Hom.: 22067 Cov.: 32 AF XY: 0.526 AC XY: 39120 AN XY: 74306

African (AFR) AF: 0.404 AC: 16762 AN: 41460

American (AMR) AF: 0.489 AC: 7460 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.707 AC: 2456 AN: 3472

East Asian (EAS) AF: 0.332 AC: 1718 AN: 5170

South Asian (SAS) AF: 0.569 AC: 2747 AN: 4828

European-Finnish (FIN) AF: 0.583 AC: 6151 AN: 10558

Middle Eastern (MID) AF: 0.718 AC: 211 AN: 294

European-Non Finnish (NFE) AF: 0.605 AC: 41122 AN: 67968

Other (OTH) AF: 0.563 AC: 1186 AN: 2106

Alfa AF: 0.428 Hom.: 1218

Bravo AF: 0.515

Asia WGS AF: 0.436 AC: 1517 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.3
DANN	Benign	0.92
PhyloP100		-0.22
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6073435; hg19: chr20-43053588;