20-44406020-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_175914.5(HNF4A):c.50-38T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.453 in 1,592,492 control chromosomes in the GnomAD database, including 170,016 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.46 ( 16380 hom., cov: 33)

Exomes 𝑓: 0.45 ( 153636 hom. )

Consequence

HNF4A
NM_175914.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.608

Publications

25 publications found

Variant links:

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

HNF4A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 20-44406020-T-C is Benign according to our data. Variant chr20-44406020-T-C is described in ClinVar as Benign. ClinVar VariationId is 673538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.757 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF4A	NM_175914.5 link	c.50-38T>C		intron_variant	Intron 1 of 9	ENST00000316673.9	NP_787110.2	P41235-5F1D8T0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF4A	ENST00000316673.9 link	c.50-38T>C		intron_variant	Intron 1 of 9	1	NM_175914.5	ENSP00000315180.4		P41235-5

Frequencies

GnomAD3 genomes

AF:

0.457

AC:

69419

AN:

151974

Hom.:

16354

Cov.:

show subpopulations

Gnomad AFR

AF:

0.448

Gnomad AMI

AF:

0.509

Gnomad AMR

AF:

0.472

Gnomad ASJ

AF:

0.424

Gnomad EAS

AF:

0.777

Gnomad SAS

AF:

0.675

Gnomad FIN

AF:

0.444

Gnomad MID

AF:

0.453

Gnomad NFE

AF:

0.422

Gnomad OTH

AF:

0.446

GnomAD2 exomes

AF:

0.501

AC:

124241

AN:

248142

AF XY:

0.505

show subpopulations

Gnomad AFR exome

AF:

0.450

Gnomad AMR exome

AF:

0.538

Gnomad ASJ exome

AF:

0.424

Gnomad EAS exome

AF:

0.793

Gnomad FIN exome

AF:

0.440

Gnomad NFE exome

AF:

0.423

Gnomad OTH exome

AF:

0.456

GnomAD4 exome

AF:

0.453

AC:

652667

AN:

1440400

Hom.:

153636

Cov.:

AF XY:

0.459

AC XY:

329699

AN XY:

717758

show subpopulations

African (AFR)

AF:

0.442

AC:

14669

AN:

33154

American (AMR)

AF:

0.526

AC:

23521

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.417

AC:

10859

AN:

26014

East Asian (EAS)

AF:

0.766

AC:

30351

AN:

39634

South Asian (SAS)

AF:

0.662

AC:

56841

AN:

85850

European-Finnish (FIN)

AF:

0.450

AC:

23104

AN:

51348

Middle Eastern (MID)

AF:

0.420

AC:

1731

AN:

4122

European-Non Finnish (NFE)

AF:

0.423

AC:

463908

AN:

1095958

Other (OTH)

AF:

0.464

AC:

27683

AN:

59622

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

16422

32844

49266

65688

82110

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14358

28716

43074

57432

71790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.457

AC:

69488

AN:

152092

Hom.:

16380

Cov.:

AF XY:

0.462

AC XY:

34389

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.448

AC:

18580

AN:

41492

American (AMR)

AF:

0.473

AC:

7224

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.424

AC:

1470

AN:

3470

East Asian (EAS)

AF:

0.777

AC:

4014

AN:

5164

South Asian (SAS)

AF:

0.675

AC:

3259

AN:

4830

European-Finnish (FIN)

AF:

0.444

AC:

4697

AN:

10578

Middle Eastern (MID)

AF:

0.456

AC:

134

AN:

294

European-Non Finnish (NFE)

AF:

0.422

AC:

28697

AN:

67970

Other (OTH)

AF:

0.451

AC:

949

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1926

3853

5779

7706

9632

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

646

1292

1938

2584

3230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.430

Hom.:

25324

Bravo

AF:

0.456

Asia WGS

AF:

0.686

AC:

2384

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 14, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Maturity onset diabetes mellitus in young

Benign:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

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 rs736824 in MODY, yet. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

3.1

(source)

DANN

Benign

0.27

PhyloP100

-0.61

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over