8-75551433-T-C

Position:

• chr8-75551433-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004133.5(HNF4G):​c.428T>C​(p.Phe143Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF4G NM_004133.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.25

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09415308).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNF4G	NM_004133.5	c.428T>C	p.Phe143Ser	missense_variant	4/10	ENST00000396423.4	NP_004124.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF4G	ENST00000396423.4	c.428T>C	p.Phe143Ser	missense_variant	4/10	1	NM_004133.5	ENSP00000379701.3
HNF4G	ENST00000354370.5	c.287T>C	p.Phe96Ser	missense_variant	5/11	1		ENSP00000346339.1
HNF4G	ENST00000674002.1	c.398T>C	p.Phe133Ser	missense_variant	4/10			ENSP00000501146.1
HNF4G	ENST00000396419.5	n.284T>C		non_coding_transcript_exon_variant	4/5	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 26, 2024

The c.398T>C (p.F133S) alteration is located in exon 4 (coding exon 4) of the HNF4G gene. This alteration results from a T to C substitution at nucleotide position 398, causing the phenylalanine (F) at amino acid position 133 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	0.067
BayesDel_addAF	Benign	-0.0039	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Benign	0.31	T;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.27	T;T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.094	T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.36	N;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.20
Sift	Benign	0.38	T;T
Sift4G	Benign	0.44	T;T
Polyphen		0.0	B;.
Vest4		0.38
MutPred		0.33		Loss of stability (P = 0.0024);.;
MVP		0.36
MPC		0.32
ClinPred		0.17	T
GERP RS		1.2
Varity_R		0.089
gMVP		0.42

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-76463668;