NM_175914.5:c.320-1419A>C

Variant names:

• chr20-44412275-A-C
• rs6073432
• NM_175914.5:c.320-1419A>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.320-1419A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.324 in 151,908 control chromosomes in the GnomAD database, including 8,119 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 0.32 (8119 hom., cov: 31)
• Consequence: HNF4A NM_175914.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0650
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• 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=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.394 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF4A	NM_175914.5	MANE Select	c.320-1419A>C		intron	N/A	NP_787110.2
	HNF4A	NM_000457.6		c.386-1419A>C		intron	N/A	NP_000448.3
	HNF4A	NM_001258355.2		c.365-1419A>C		intron	N/A	NP_001245284.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF4A	ENST00000316673.9	TSL:1 MANE Select	c.320-1419A>C		intron	N/A	ENSP00000315180.4	P41235-5
	HNF4A	ENST00000316099.10	TSL:1	c.386-1419A>C		intron	N/A	ENSP00000312987.3	P41235-1
	HNF4A	ENST00000415691.2	TSL:1	c.386-1419A>C		intron	N/A	ENSP00000412111.1	P41235-2

Frequencies

GnomAD3 genomes AF: 0.324 AC: 49243 AN: 151790 Hom.: 8102 Cov.: 31

Gnomad AFR AF: 0.314

Gnomad AMI AF: 0.426

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.410

Gnomad EAS AF: 0.305

Gnomad SAS AF: 0.410

Gnomad FIN AF: 0.383

Gnomad MID AF: 0.433

Gnomad NFE AF: 0.333

Gnomad OTH AF: 0.327

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

GnomAD4 genome AF: 0.324 AC: 49277 AN: 151908 Hom.: 8119 Cov.: 31 AF XY: 0.327 AC XY: 24260 AN XY: 74244

African (AFR) AF: 0.314 AC: 12995 AN: 41416

American (AMR) AF: 0.224 AC: 3424 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.410 AC: 1420 AN: 3466

East Asian (EAS) AF: 0.305 AC: 1574 AN: 5156

South Asian (SAS) AF: 0.409 AC: 1967 AN: 4806

European-Finnish (FIN) AF: 0.383 AC: 4037 AN: 10550

Middle Eastern (MID) AF: 0.432 AC: 126 AN: 292

European-Non Finnish (NFE) AF: 0.333 AC: 22647 AN: 67934

Other (OTH) AF: 0.332 AC: 699 AN: 2108

Alfa AF: 0.322 Hom.: 4646

Bravo AF: 0.309

Asia WGS AF: 0.367 AC: 1275 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.1
DANN	Benign	0.66
PhyloP100		-0.065
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: rs6073432; hg19: chr20-43040915;