rs11086926

Positions:

• chr20-44430057-T-G

Variant summary

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

The ENST00000316673.9(HNF4A):​c.*392T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 206,482 control chromosomes in the GnomAD database, including 1,906 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1767 hom., cov: 32)
  • Exomes 𝑓: 0.058 (139 hom.)
• Consequence: HNF4A ENST00000316673.9 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0710

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=-0.9).
• BP6: Variant 20-44430057-T-G is Benign according to our data. Variant chr20-44430057-T-G is described in ClinVar as [Benign]. Clinvar id is 338440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.255 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNF4A	NM_175914.5	c.*392T>G		3_prime_UTR_variant	10/10	ENST00000316673.9	NP_787110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF4A	ENST00000316673.9	c.*392T>G		3_prime_UTR_variant	10/10	1	NM_175914.5	ENSP00000315180
HNF4A	ENST00000316099.10	c.*392T>G		3_prime_UTR_variant	10/10	1		ENSP00000312987
HNF4A	ENST00000415691.2	c.*392T>G		3_prime_UTR_variant	10/10	1		ENSP00000412111	P1
HNF4A	ENST00000372920.1	c.*1584T>G		3_prime_UTR_variant, NMD_transcript_variant	11/11	1		ENSP00000362011

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19185 AN: 152050 Hom.: 1760 Cov.: 32

Gnomad AFR AF: 0.259

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.131

Gnomad ASJ AF: 0.0499

Gnomad EAS AF: 0.0345

Gnomad SAS AF: 0.0992

Gnomad FIN AF: 0.0610

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0691

Gnomad OTH AF: 0.107

GnomAD4 exome AF: 0.0583 AC: 3167 AN: 54314 Hom.: 139 Cov.: 0 AF XY: 0.0592 AC XY: 1653 AN XY: 27938

Gnomad4 AFR exome AF: 0.223

Gnomad4 AMR exome AF: 0.107

Gnomad4 ASJ exome AF: 0.0379

Gnomad4 EAS exome AF: 0.0309

Gnomad4 SAS exome AF: 0.0598

Gnomad4 FIN exome AF: 0.0413

Gnomad4 NFE exome AF: 0.0511

Gnomad4 OTH exome AF: 0.0688

GnomAD4 genome AF: 0.126 AC: 19211 AN: 152168 Hom.: 1767 Cov.: 32 AF XY: 0.124 AC XY: 9220 AN XY: 74392

Gnomad4 AFR AF: 0.259

Gnomad4 AMR AF: 0.131

Gnomad4 ASJ AF: 0.0499

Gnomad4 EAS AF: 0.0349

Gnomad4 SAS AF: 0.0982

Gnomad4 FIN AF: 0.0610

Gnomad4 NFE AF: 0.0691

Gnomad4 OTH AF: 0.106

Alfa AF: 0.0965 Hom.: 457

Bravo AF: 0.138

Asia WGS AF: 0.0890 AC: 309 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Familial hyperinsulinism Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Maturity-onset diabetes of the young type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.3
DANN	Benign	0.50

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: rs11086926; hg19: chr20-43058697;