rs11574739

Positions:

• chr20-44414310-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_175914.5(HNF4A):​c.427-197A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 152,168 control chromosomes in the GnomAD database, including 2,936 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.19 (2936 hom., cov: 32)
• Consequence: HNF4A NM_175914.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.114

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 20-44414310-A-C is Benign according to our data. Variant chr20-44414310-A-C is described in ClinVar as [Benign]. Clinvar id is 676908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.21 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNF4A	NM_175914.5	c.427-197A>C		intron_variant		ENST00000316673.9	NP_787110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF4A	ENST00000316673.9	c.427-197A>C		intron_variant		1	NM_175914.5	ENSP00000315180

Frequencies

GnomAD3 genomes AF: 0.191 AC: 29087 AN: 152050 Hom.: 2936 Cov.: 32

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.166

Gnomad AMR AF: 0.208

Gnomad ASJ AF: 0.182

Gnomad EAS AF: 0.0166

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.203

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

GnomAD4 genome AF: 0.191 AC: 29100 AN: 152168 Hom.: 2936 Cov.: 32 AF XY: 0.186 AC XY: 13845 AN XY: 74372

Gnomad4 AFR AF: 0.214

Gnomad4 AMR AF: 0.207

Gnomad4 ASJ AF: 0.182

Gnomad4 EAS AF: 0.0170

Gnomad4 SAS AF: 0.139

Gnomad4 FIN AF: 0.119

Gnomad4 NFE AF: 0.203

Gnomad4 OTH AF: 0.202

Alfa AF: 0.196 Hom.: 1182

Bravo AF: 0.198

Asia WGS AF: 0.0930 AC: 325 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Maturity onset diabetes mellitus in young Benign:1

Benign, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Potent mutations in HNF4A are associated with poor insulin secretion in response to hyperglycemia. Associated with MODY1. Patients initially respond well to sulfonylureas but eventually become insulin dependent. However, more evidence is required to ascertain the role of this particular variant rs11574739 in MODY, yet. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	5.9
DANN	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11574739; hg19: chr20-43042950;