20-44430797-C-T

Position:

• chr20-44430797-C-T

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.*1132C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.25 in 152,172 control chromosomes in the GnomAD database, including 6,867 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (6859 hom., cov: 30)
  • Exomes 𝑓: 0.15 (8 hom.)
• Consequence: HNF4A NM_175914.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.919

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=-0.83).
• BP6: Variant 20-44430797-C-T is Benign according to our data. Variant chr20-44430797-C-T is described in ClinVar as [Benign]. Clinvar id is 338458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.578 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNF4A	NM_175914.5	c.*1132C>T		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.*1132C>T		3_prime_UTR_variant	10/10	1	NM_175914.5	ENSP00000315180
HNF4A	ENST00000316099.10	c.*1132C>T		3_prime_UTR_variant	10/10	1		ENSP00000312987
HNF4A	ENST00000372920.1	c.*2324C>T		3_prime_UTR_variant, NMD_transcript_variant	11/11	1		ENSP00000362011

Frequencies

GnomAD3 genomes AF: 0.250 AC: 37975 AN: 151622 Hom.: 6833 Cov.: 30

Gnomad AFR AF: 0.455

Gnomad AMI AF: 0.0978

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.595

Gnomad SAS AF: 0.289

Gnomad FIN AF: 0.0959

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.224

GnomAD4 exome AF: 0.153 AC: 66 AN: 432 Hom.: 8 Cov.: 0 AF XY: 0.167 AC XY: 47 AN XY: 282

Gnomad4 AFR exome AF: 0.750

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.214

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 0.100

Gnomad4 NFE exome AF: 0.113

Gnomad4 OTH exome AF: 0.278

GnomAD4 genome AF: 0.251 AC: 38046 AN: 151740 Hom.: 6859 Cov.: 30 AF XY: 0.254 AC XY: 18837 AN XY: 74154

Gnomad4 AFR AF: 0.454

Gnomad4 AMR AF: 0.318

Gnomad4 ASJ AF: 0.122

Gnomad4 EAS AF: 0.596

Gnomad4 SAS AF: 0.289

Gnomad4 FIN AF: 0.0959

Gnomad4 NFE AF: 0.117

Gnomad4 OTH AF: 0.231

Alfa AF: 0.185 Hom.: 2352

Bravo AF: 0.277

Asia WGS AF: 0.444 AC: 1541 AN: 3476

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 28, 2020	This variant is associated with the following publications: (PMID: 31461081) -

Familial hyperinsulinism Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 13, 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	-0.83
CADD	Benign	2.4
DANN	Benign	0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs6130615; hg19: chr20-43059437;