dbSNP rs6017341: HNF4A:c.*4981C>G (chr20-44434646-C-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The NM_001258355.2(HNF4A):c.*4981C>G variant causes a downstream gene change. The variant allele was found at a frequency of 0.0749 in 152,220 control chromosomes in the GnomAD database, including 655 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.075 ( 655 hom., cov: 30)

Exomes 𝑓: 0.011 ( 0 hom. )

Consequence

HNF4A
NM_001258355.2 downstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.72

Publications

2 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.28).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Protein
HNF4A	NM_001258355.2 link	c.*4981C>G	downstream_gene_variant	NP_001245284.1
HNF4A	NM_178849.3 link	c.*4981C>G	downstream_gene_variant	NP_849180.1
HNF4A	NM_001030003.3 link	c.*4981C>G	downstream_gene_variant	NP_001025174.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD3 genomes

AF:

0.0749

AC:

11382

AN:

152010

Hom.:

654

Cov.:

show subpopulations

Gnomad AFR

AF:

0.160

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.106

Gnomad ASJ

AF:

0.0392

Gnomad EAS

AF:

0.00905

Gnomad SAS

AF:

0.0234

Gnomad FIN

AF:

0.0160

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0365

Gnomad OTH

AF:

0.0721

GnomAD4 exome

AF:

0.0109

AC:

AN:

Hom.:

Cov.:

AF XY:

0.0161

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0749

AC:

11400

AN:

152128

Hom.:

655

Cov.:

AF XY:

0.0714

AC XY:

5309

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.160

AC:

6642

AN:

41454

American (AMR)

AF:

0.106

AC:

1622

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0392

AC:

136

AN:

3470

East Asian (EAS)

AF:

0.00888

AC:

AN:

5180

South Asian (SAS)

AF:

0.0234

AC:

113

AN:

4822

European-Finnish (FIN)

AF:

0.0160

AC:

169

AN:

10586

Middle Eastern (MID)

AF:

0.0748

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0366

AC:

2486

AN:

68016

Other (OTH)

AF:

0.0714

AC:

151

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

523

1045

1568

2090

2613

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

232

348

464

580

<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:

0.0188

Hom.:

Bravo

AF:

0.0874

Asia WGS

AF:

0.0260

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.85

PhyloP100

3.7

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over