rs6103731

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.670+141A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.553 in 653,248 control chromosomes in the GnomAD database, including 102,511 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.55 ( 23129 hom., cov: 32)

Exomes 𝑓: 0.55 ( 79382 hom. )

Consequence

HNF4A
NM_175914.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.431

Publications

9 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=-0.88).

BP6

Variant 20-44418653-A-G is Benign according to our data. Variant chr20-44418653-A-G is described in ClinVar as Benign. ClinVar VariationId is 676879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.587 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF4A	NM_175914.5 link	c.670+141A>G		intron_variant	Intron 6 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.670+141A>G		intron_variant	Intron 6 of 9	1	NM_175914.5	ENSP00000315180.4		P41235-5

Frequencies

GnomAD3 genomes

AF:

0.547

AC:

83173

AN:

151940

Hom.:

23120

Cov.:

show subpopulations

Gnomad AFR

AF:

0.520

Gnomad AMI

AF:

0.613

Gnomad AMR

AF:

0.500

Gnomad ASJ

AF:

0.702

Gnomad EAS

AF:

0.294

Gnomad SAS

AF:

0.481

Gnomad FIN

AF:

0.528

Gnomad MID

AF:

0.671

Gnomad NFE

AF:

0.592

Gnomad OTH

AF:

0.572

GnomAD4 exome

AF:

0.554

AC:

277904

AN:

501190

Hom.:

79382

AF XY:

0.552

AC XY:

146613

AN XY:

265428

show subpopulations

African (AFR)

AF:

0.524

AC:

7462

AN:

14242

American (AMR)

AF:

0.442

AC:

11375

AN:

25730

Ashkenazi Jewish (ASJ)

AF:

0.692

AC:

10528

AN:

15220

East Asian (EAS)

AF:

0.310

AC:

9909

AN:

31948

South Asian (SAS)

AF:

0.492

AC:

25564

AN:

52008

European-Finnish (FIN)

AF:

0.546

AC:

17240

AN:

31594

Middle Eastern (MID)

AF:

0.638

AC:

1374

AN:

2152

European-Non Finnish (NFE)

AF:

0.595

AC:

178649

AN:

300308

Other (OTH)

AF:

0.565

AC:

15803

AN:

27988

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

6003

12006

18010

24013

30016

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1112

2224

3336

4448

5560

<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:

0.547

AC:

83221

AN:

152058

Hom.:

23129

Cov.:

AF XY:

0.541

AC XY:

40217

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.520

AC:

21544

AN:

41464

American (AMR)

AF:

0.499

AC:

7633

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.702

AC:

2436

AN:

3470

East Asian (EAS)

AF:

0.294

AC:

1522

AN:

5176

South Asian (SAS)

AF:

0.479

AC:

2312

AN:

4822

European-Finnish (FIN)

AF:

0.528

AC:

5576

AN:

10560

Middle Eastern (MID)

AF:

0.667

AC:

196

AN:

294

European-Non Finnish (NFE)

AF:

0.592

AC:

40233

AN:

67968

Other (OTH)

AF:

0.574

AC:

1210

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1931

3863

5794

7726

9657

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

718

1436

2154

2872

3590

<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:

0.574

Hom.:

37611

Bravo

AF:

0.544

Asia WGS

AF:

0.404

AC:

1404

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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 rs6103731 in MODY, yet. -

not provided

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.84

(source)

DANN

Benign

0.85

PhyloP100

-0.43

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