Genetic Variant HNF4A:c.50-10649G>T (chr20-44395409-G-T) – 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.50-10649G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 152,334 control chromosomes in the GnomAD database, including 15,263 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 0.42 ( 15250 hom., cov: 33)

Exomes 𝑓: 0.50 ( 13 hom. )

Consequence

HNF4A
NM_175914.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.170

Publications

25 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 links:

HNF4A-AS1 (HGNC:49505): (HNF4A antisense RNA 1)

HNF4A-AS1 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=-0.81).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.567 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175914.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HNF4A	NM_175914.5	MANE Select	c.50-10649G>T	intron	N/A	NP_787110.2
HNF4A	NM_001287183.2		c.40+4730G>T	intron	N/A	NP_001274112.1
HNF4A	NM_001030003.3		c.50-10649G>T	intron	N/A	NP_001025174.1	P41235-6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HNF4A	ENST00000316673.9	TSL:1 MANE Select	c.50-10649G>T	intron	N/A	ENSP00000315180.4	P41235-5
HNF4A	ENST00000457232.5	TSL:1	c.50-10649G>T	intron	N/A	ENSP00000396216.1	P41235-6
HNF4A	ENST00000609795.5	TSL:1	c.50-10649G>T	intron	N/A	ENSP00000476609.1	P41235-7

Frequencies

GnomAD3 genomes

AF:

0.421

AC:

64102

AN:

152112

Hom.:

15239

Cov.:

show subpopulations

Gnomad AFR

AF:

0.186

Gnomad AMI

AF:

0.390

Gnomad AMR

AF:

0.577

Gnomad ASJ

AF:

0.438

Gnomad EAS

AF:

0.493

Gnomad SAS

AF:

0.357

Gnomad FIN

AF:

0.506

Gnomad MID

AF:

0.434

Gnomad NFE

AF:

0.515

Gnomad OTH

AF:

0.452

GnomAD4 exome

AF:

0.500

AC:

AN:

102

Hom.:

Cov.:

AF XY:

0.480

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.250

AC:

AN:

American (AMR)

AF:

0.833

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.300

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.600

AC:

AN:

Middle Eastern (MID)

AF:

0.500

AC:

AN:

European-Non Finnish (NFE)

AF:

0.468

AC:

AN:

Other (OTH)

AF:

0.750

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.421

AC:

64129

AN:

152232

Hom.:

15250

Cov.:

AF XY:

0.424

AC XY:

31528

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.186

AC:

7717

AN:

41554

American (AMR)

AF:

0.577

AC:

8835

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.438

AC:

1519

AN:

3472

East Asian (EAS)

AF:

0.493

AC:

2551

AN:

5172

South Asian (SAS)

AF:

0.356

AC:

1723

AN:

4834

European-Finnish (FIN)

AF:

0.506

AC:

5360

AN:

10590

Middle Eastern (MID)

AF:

0.429

AC:

126

AN:

294

European-Non Finnish (NFE)

AF:

0.515

AC:

34988

AN:

67988

Other (OTH)

AF:

0.452

AC:

955

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1812

3624

5436

7248

9060

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

588

1176

1764

2352

2940

<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:

0.490

Hom.:

78785

Bravo

AF:

0.421

Asia WGS

AF:

0.408

AC:

1419

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

2.4

(source)

DANN

Benign

0.47

PhyloP100

0.17

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over