chr20-44430057-T-G

Variant names:

• chr20-44430057-T-G
• rs11086926
• ENST00000372920.1:n.*1584T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000372920.1(HNF4A):​n.*1584T>G variant causes a non coding transcript exon 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 ENST00000372920.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0710
• Publications: 16 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 -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 VariationId 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 rank	MANE	Protein	UniProt
HNF4A	NM_175914.5	c.*392T>G		3_prime_UTR_variant	Exon 10 of 10	ENST00000316673.9	NP_787110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF4A	ENST00000316673.9	c.*392T>G		3_prime_UTR_variant	Exon 10 of 10	1	NM_175914.5	ENSP00000315180.4

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

African (AFR) AF: 0.223 AC: 302 AN: 1354

American (AMR) AF: 0.107 AC: 274 AN: 2560

Ashkenazi Jewish (ASJ) AF: 0.0379 AC: 55 AN: 1452

East Asian (EAS) AF: 0.0309 AC: 71 AN: 2298

South Asian (SAS) AF: 0.0598 AC: 371 AN: 6202

European-Finnish (FIN) AF: 0.0413 AC: 117 AN: 2836

Middle Eastern (MID) AF: 0.0488 AC: 12 AN: 246

European-Non Finnish (NFE) AF: 0.0511 AC: 1746 AN: 34182

Other (OTH) AF: 0.0688 AC: 219 AN: 3184

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

African (AFR) AF: 0.259 AC: 10759 AN: 41486

American (AMR) AF: 0.131 AC: 2004 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0499 AC: 173 AN: 3468

East Asian (EAS) AF: 0.0349 AC: 181 AN: 5180

South Asian (SAS) AF: 0.0982 AC: 473 AN: 4816

European-Finnish (FIN) AF: 0.0610 AC: 647 AN: 10614

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0691 AC: 4701 AN: 67998

Other (OTH) AF: 0.106 AC: 225 AN: 2116

Alfa AF: 0.0981 Hom.: 683

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

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Familial hyperinsulinism Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.071
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: rs11086926; hg19: chr20-43058697;