Genetic Variant HNF4A:c.-83C>G (chr20-44355722-C-G) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS2_Supporting

The NM_175914.5(HNF4A):c.-83C>G variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.00000451 in 1,107,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. The gene HNF4A is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000045 ( 0 hom. )

Consequence

HNF4A
NM_175914.5 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.60

Publications

1 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:

R3HDML-AS1 (HGNC:55830): (R3HDML antisense RNA 1)

R3HDML-AS1 links:

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new If you want to explore the variant's impact on the transcript NM_175914.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Specifications for HNF4A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.34).

BS2

High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.-83C>G	5_prime_UTR	Exon 1 of 10	NP_787110.2
HNF4A	NM_001287183.2		c.-314C>G	5_prime_UTR	Exon 1 of 11	NP_001274112.1
HNF4A	NM_001030003.3		c.-83C>G	5_prime_UTR	Exon 1 of 10	NP_001025174.1	P41235-6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HNF4A	ENST00000316673.9	TSL:1 MANE Select	c.-83C>G	5_prime_UTR	Exon 1 of 10	ENSP00000315180.4	P41235-5
HNF4A	ENST00000894460.1		c.-83C>G	5_prime_UTR	Exon 1 of 9	ENSP00000564519.1
HNF4A	ENST00000457232.5	TSL:1	c.-83C>G	upstream_gene	N/A	ENSP00000396216.1	P41235-6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000451

AC:

AN:

1107566

Hom.:

Cov.:

AF XY:

0.00000353

AC XY:

AN XY:

566922

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26720

American (AMR)

AF:

0.00

AC:

AN:

43374

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23834

East Asian (EAS)

AF:

0.00

AC:

AN:

37860

South Asian (SAS)

AF:

0.0000382

AC:

AN:

78566

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50504

Middle Eastern (MID)

AF:

0.000230

AC:

AN:

4340

European-Non Finnish (NFE)

AF:

0.00000126

AC:

AN:

793920

Other (OTH)

AF:

0.00

AC:

AN:

48448

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.535

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.92

PhyloP100

3.6

PromoterAI

-0.12

Neutral

(source)

Mutation Taster

=297/3

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over