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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000372920.1. 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.*392T>G		3_prime_UTR	Exon 10 of 10	NP_787110.2
	HNF4A	NM_000457.6		c.*392T>G		3_prime_UTR	Exon 10 of 10	NP_000448.3
	HNF4A	NM_001258355.2		c.*392T>G		3_prime_UTR	Exon 11 of 11	NP_001245284.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF4A	ENST00000372920.1	TSL:1	n.*1584T>G		non_coding_transcript_exon	Exon 11 of 11	ENSP00000362011.1
	HNF4A	ENST00000316673.9	TSL:1 MANE Select	c.*392T>G		3_prime_UTR	Exon 10 of 10	ENSP00000315180.4
	HNF4A	ENST00000316099.10	TSL:1	c.*392T>G		3_prime_UTR	Exon 10 of 10	ENSP00000312987.3

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Familial hyperinsulinism (1)
-	-	1	Maturity-onset diabetes of the young type 1 (1)

Computational scores

Source: dbNSFP v4.9

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;