8-75564008-A-G

Variant summary

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

The NM_004133.5(HNF4G):c.1280A>G(p.Gln427Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HNF4G NM_004133.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.95

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]

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=0.18131131).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF4G	NM_004133.5	c.1280A>G	p.Gln427Arg	missense_variant	10/10	ENST00000396423.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF4G	ENST00000396423.4	c.1280A>G	p.Gln427Arg	missense_variant	10/10	1	NM_004133.5
HNF4G	ENST00000354370.5	c.1139A>G	p.Gln380Arg	missense_variant	11/11	1		P1
HNF4G	ENST00000674002.1	c.1250A>G	p.Gln417Arg	missense_variant	10/10

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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 29, 2023

The c.1250A>G (p.Q417R) alteration is located in exon 10 (coding exon 10) of the HNF4G gene. This alteration results from a A to G substitution at nucleotide position 1250, causing the glutamine (Q) at amino acid position 417 to be replaced by an arginine (R). 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	0.13
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.37	T;.
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.34	T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	0.74	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.79	N;N
REVEL	Benign	0.17
Sift	Benign	0.52	T;T
Sift4G	Benign	0.52	T;T
Polyphen		0.24	B;.
Vest4		0.28
MutPred		0.21		Loss of loop (P = 0.0374);.;
MVP		0.67
MPC		0.24
ClinPred		0.63	D
GERP RS		5.6
Varity_R		0.19
gMVP		0.43

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: chr8-76476243;