NM_175914.5:c.50-6308A>G

Variant names:

• chr20-44399750-A-G
• rs3212172
• NM_175914.5:c.50-6308A>G

Variant summary

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

The NM_175914.5(HNF4A):​c.50-6308A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 152,028 control chromosomes in the GnomAD database, including 3,545 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 0.20 (3545 hom., cov: 31)
• Consequence: HNF4A NM_175914.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0260
• Publications: 7 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=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.313 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF4A	NM_175914.5	MANE Select	c.50-6308A>G		intron	N/A	NP_787110.2
	HNF4A	NM_001287183.2		c.41-6308A>G		intron	N/A	NP_001274112.1
	HNF4A	NM_001030003.3		c.50-6308A>G		intron	N/A	NP_001025174.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF4A	ENST00000316673.9	TSL:1 MANE Select	c.50-6308A>G		intron	N/A	ENSP00000315180.4
	HNF4A	ENST00000457232.5	TSL:1	c.50-6308A>G		intron	N/A	ENSP00000396216.1
	HNF4A	ENST00000609795.5	TSL:1	c.50-6308A>G		intron	N/A	ENSP00000476609.1

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30277 AN: 151910 Hom.: 3541 Cov.: 31

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.227

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.203

Gnomad EAS AF: 0.271

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.210

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

GnomAD4 genome AF: 0.199 AC: 30285 AN: 152028 Hom.: 3545 Cov.: 31 AF XY: 0.199 AC XY: 14821 AN XY: 74346

African (AFR) AF: 0.317 AC: 13137 AN: 41398

American (AMR) AF: 0.144 AC: 2197 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 706 AN: 3470

East Asian (EAS) AF: 0.271 AC: 1401 AN: 5176

South Asian (SAS) AF: 0.227 AC: 1094 AN: 4820

European-Finnish (FIN) AF: 0.120 AC: 1270 AN: 10590

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.143 AC: 9738 AN: 68004

Other (OTH) AF: 0.211 AC: 445 AN: 2110

Alfa AF: 0.156 Hom.: 2674

Bravo AF: 0.204

Asia WGS AF: 0.237 AC: 827 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.87
DANN	Benign	0.71
PhyloP100		-0.026
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs3212172; hg19: chr20-43028390;