dbSNP rs717248: HNF4A:c.50-9093T>C (chr20-44396965-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_175914.5(HNF4A):c.50-9093T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0773 in 152,154 control chromosomes in the GnomAD database, including 738 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 0.077 ( 738 hom., cov: 32)

Consequence

HNF4A
NM_175914.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0850

Publications

8 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF4A	NM_175914.5 link	c.50-9093T>C		intron_variant	Intron 1 of 9	ENST00000316673.9	NP_787110.2	P41235-5F1D8T0

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
HNF4A	ENST00000316673.9 link	c.50-9093T>C	intron_variant	Intron 1 of 9	1	NM_175914.5	ENSP00000315180.4	P41235-5
HNF4A	ENST00000457232.5 link	c.50-9093T>C	intron_variant	Intron 1 of 9	1		ENSP00000396216.1	P41235-6
HNF4A	ENST00000609795.5 link	c.50-9093T>C	intron_variant	Intron 1 of 7	1		ENSP00000476609.1	P41235-7
HNF4A	ENST00000609262.5 link	c.40+6286T>C	intron_variant	Intron 2 of 3	1		ENSP00000476310.1	B9VVT8

Frequencies

GnomAD3 genomes

AF:

0.0773

AC:

11758

AN:

152038

Hom.:

740

Cov.:

show subpopulations

Gnomad AFR

AF:

0.177

Gnomad AMI

AF:

0.0209

Gnomad AMR

AF:

0.0439

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0454

Gnomad FIN

AF:

0.0531

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0413

Gnomad OTH

AF:

0.0622

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0773

AC:

11764

AN:

152154

Hom.:

738

Cov.:

AF XY:

0.0758

AC XY:

5640

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.176

AC:

7315

AN:

41470

American (AMR)

AF:

0.0439

AC:

671

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00634

AC:

AN:

3468

East Asian (EAS)

AF:

0.000579

AC:

AN:

5184

South Asian (SAS)

AF:

0.0452

AC:

218

AN:

4824

European-Finnish (FIN)

AF:

0.0531

AC:

563

AN:

10594

Middle Eastern (MID)

AF:

0.0548

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0413

AC:

2807

AN:

68002

Other (OTH)

AF:

0.0616

AC:

130

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

531

1062

1594

2125

2656

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

256

384

512

640

<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:

0.0519

Hom.:

601

Bravo

AF:

0.0808

Asia WGS

AF:

0.0360

AC:

124

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

3.2

(source)

DANN

Benign

0.68

PhyloP100

0.085

Mutation Taster

=100/0

polymorphism (auto)

(source)

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