rs3746575

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.1217-67C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.589 in 1,595,626 control chromosomes in the GnomAD database, including 279,916 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene HNF4A is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.57 ( 24593 hom., cov: 28)

Exomes 𝑓: 0.59 ( 255323 hom. )

Consequence

HNF4A
NM_175914.5 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.378

Publications

13 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
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

new If you want to explore the variant's impact on the transcript NM_175914.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Specifications for HNF4A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 20-44429456-C-G is Benign according to our data. Variant chr20-44429456-C-G is described in ClinVar as Benign. ClinVar VariationId is 676886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.602 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175914.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
HNF4A	NM_175914.5	MANE Select	c.1217-67C>G	intron	N/A	NP_787110.2
HNF4A	NM_000457.6		c.1283-67C>G	intron	N/A	NP_000448.3
HNF4A	NM_001258355.2		c.1262-67C>G	intron	N/A	NP_001245284.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HNF4A	ENST00000316673.9	TSL:1 MANE Select	c.1217-67C>G	intron	N/A	ENSP00000315180.4	P41235-5
HNF4A	ENST00000316099.10	TSL:1	c.1283-67C>G	intron	N/A	ENSP00000312987.3	P41235-1
HNF4A	ENST00000415691.2	TSL:1	c.1253-67C>G	intron	N/A	ENSP00000412111.1	P41235-2

Frequencies

GnomAD3 genomes

AF:

0.567

AC:

85607

AN:

151020

Hom.:

24597

Cov.:

show subpopulations

Gnomad AFR

AF:

0.530

Gnomad AMI

AF:

0.609

Gnomad AMR

AF:

0.503

Gnomad ASJ

AF:

0.706

Gnomad EAS

AF:

0.353

Gnomad SAS

AF:

0.585

Gnomad FIN

AF:

0.578

Gnomad MID

AF:

0.717

Gnomad NFE

AF:

0.607

Gnomad OTH

AF:

0.584

GnomAD4 exome

AF:

0.591

AC:

853730

AN:

1444488

Hom.:

255323

AF XY:

0.593

AC XY:

426397

AN XY:

719238

show subpopulations

African (AFR)

AF:

0.529

AC:

17520

AN:

33126

American (AMR)

AF:

0.429

AC:

19133

AN:

44582

Ashkenazi Jewish (ASJ)

AF:

0.702

AC:

18219

AN:

25970

East Asian (EAS)

AF:

0.382

AC:

15095

AN:

39566

South Asian (SAS)

AF:

0.602

AC:

51605

AN:

85772

European-Finnish (FIN)

AF:

0.597

AC:

31792

AN:

53230

Middle Eastern (MID)

AF:

0.678

AC:

3771

AN:

5564

European-Non Finnish (NFE)

AF:

0.603

AC:

661551

AN:

1096890

Other (OTH)

AF:

0.586

AC:

35044

AN:

59788

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

16586

33173

49759

66346

82932

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17748

35496

53244

70992

88740

<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:

0.567

AC:

85635

AN:

151138

Hom.:

24593

Cov.:

AF XY:

0.563

AC XY:

41530

AN XY:

73760

show subpopulations

African (AFR)

AF:

0.530

AC:

21800

AN:

41134

American (AMR)

AF:

0.503

AC:

7640

AN:

15198

Ashkenazi Jewish (ASJ)

AF:

0.706

AC:

2444

AN:

3464

East Asian (EAS)

AF:

0.353

AC:

1792

AN:

5078

South Asian (SAS)

AF:

0.584

AC:

2806

AN:

4802

European-Finnish (FIN)

AF:

0.578

AC:

5966

AN:

10316

Middle Eastern (MID)

AF:

0.705

AC:

206

AN:

292

European-Non Finnish (NFE)

AF:

0.607

AC:

41208

AN:

67860

Other (OTH)

AF:

0.585

AC:

1221

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1748

3496

5243

6991

8739

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

732

1464

2196

2928

3660

<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:

0.583

Hom.:

3276

Bravo

AF:

0.558

Asia WGS

AF:

0.471

AC:

1639

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Maturity-onset diabetes of the young (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.48

(source)

DANN

Benign

0.60

PhyloP100

-0.38

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over