Variant 8-75560353-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004133.5(HNF4G):c.1133A>G(p.Asn378Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,613,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

HNF4G
NM_004133.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.65

Variant links:

Genes affected

HNF4G (HGNC:5026): (hepatocyte nuclear factor 4 gamma) Enables DNA-binding transcription activator activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Involved in positive regulation of transcription by RNA polymerase II. Located in several cellular components, including intercellular bridge; mitotic spindle; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

HNF4G links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05432403).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF4G	NM_004133.5 linkuse as main transcript	c.1133A>G	p.Asn378Ser	missense_variant	9/10	ENST00000396423.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF4G	ENST00000396423.4 linkuse as main transcript	c.1133A>G	p.Asn378Ser	missense_variant	9/10	1	NM_004133.5
HNF4G	ENST00000354370.5 linkuse as main transcript	c.992A>G	p.Asn331Ser	missense_variant	10/11	1		P1	Q14541-1
HNF4G	ENST00000674002.1 linkuse as main transcript	c.1103A>G	p.Asn368Ser	missense_variant	9/10				Q14541-2

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000319

AC:

AN:

250738

Hom.:

AF XY:

0.0000517

AC XY:

AN XY:

135478

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000618

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000431

AC:

AN:

1460928

Hom.:

Cov.:

AF XY:

0.0000427

AC XY:

AN XY:

726792

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000486

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2022

The c.1103A>G (p.N368S) alteration is located in exon 9 (coding exon 9) of the HNF4G gene. This alteration results from a A to G substitution at nucleotide position 1103, causing the asparagine (N) at amino acid position 368 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.049

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.59

Cadd

Benign

1.0

Dann

Benign

0.14

DEOGEN2

Benign

0.22

T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.91

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.054

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.63

N;.

MutationTaster

Benign

0.96

D;D

PrimateAI

Benign

0.31

PROVEAN

Benign

0.40

N;N

REVEL

Benign

0.068

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0010

B;.

Vest4

0.23

MVP

0.39

MPC

0.14

ClinPred

0.016

GERP RS

-2.4

Varity_R

0.027

gMVP

0.19

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