8-75558857-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.943A>G(p.Ile315Val) 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: 1.45

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=0.090625584).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF4G	NM_004133.5	c.943A>G	p.Ile315Val	missense_variant	8/10	ENST00000396423.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF4G	ENST00000396423.4	c.943A>G	p.Ile315Val	missense_variant	8/10	1	NM_004133.5
HNF4G	ENST00000354370.5	c.802A>G	p.Ile268Val	missense_variant	9/11	1		P1
HNF4G	ENST00000674002.1	c.913A>G	p.Ile305Val	missense_variant	8/10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Jun 16, 2023

The c.913A>G (p.I305V) alteration is located in exon 8 (coding exon 8) of the HNF4G gene. This alteration results from a A to G substitution at nucleotide position 913, causing the isoleucine (I) at amino acid position 305 to be replaced by a valine (V). 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	0.060
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	12
Dann	Benign	0.53
DEOGEN2	Uncertain	0.52	D;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.091	T;T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	-0.56	N;.
MutationTaster	Benign	0.98	D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.0	N;N
REVEL	Uncertain	0.33
Sift	Benign	1.0	T;T
Sift4G	Benign	0.71	T;T
Polyphen		0.0	B;.
Vest4		0.11
MutPred		0.46		Loss of catalytic residue at I268 (P = 0.218);.;
MVP		0.26
MPC		0.15
ClinPred		0.071	T
GERP RS		3.3
Varity_R		0.20
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr8-76471092;