NM_175914.5:c.1217-67C>G

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.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 (★★).

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: 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=-0.89).

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF4A	NM_175914.5 link	c.1217-67C>G		intron_variant	Intron 9 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.1217-67C>G		intron_variant	Intron 9 of 9	1	NM_175914.5	ENSP00000315180.4		P41235-5

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

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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. -

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 rs3746575 in MODY, yet. -

Computational scores

Source: dbNSFP v4.3

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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