Variant 20-44429456-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -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

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 676886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-44429456-C-G is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
HNF4A	NM_175914.5 linkuse as main transcript	c.1217-67C>G		intron_variant		ENST00000316673.9	NP_787110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF4A	ENST00000316673.9 linkuse as main transcript	c.1217-67C>G		intron_variant		1	NM_175914.5	ENSP00000315180		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

Gnomad4 AFR exome

AF:

0.529

Gnomad4 AMR exome

AF:

0.429

Gnomad4 ASJ exome

AF:

0.702

Gnomad4 EAS exome

AF:

0.382

Gnomad4 SAS exome

AF:

0.602

Gnomad4 FIN exome

AF:

0.597

Gnomad4 NFE exome

AF:

0.603

Gnomad4 OTH exome

AF:

0.586

GnomAD4 genome

AF:

0.567

AC:

85635

AN:

151138

Hom.:

24593

Cov.:

AF XY:

0.563

AC XY:

41530

AN XY:

73760

show subpopulations

Gnomad4 AFR

AF:

0.530

Gnomad4 AMR

AF:

0.503

Gnomad4 ASJ

AF:

0.706

Gnomad4 EAS

AF:

0.353

Gnomad4 SAS

AF:

0.584

Gnomad4 FIN

AF:

0.578

Gnomad4 NFE

AF:

0.607

Gnomad4 OTH

AF:

0.585

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	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

Benign, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

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

DANN

Benign

0.60

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over