8-75553179-A-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.627A>C(p.Glu209Asp) 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. 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: -0.0360

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=0.2282877).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF4G	NM_004133.5	c.627A>C	p.Glu209Asp	missense_variant	5/10	ENST00000396423.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF4G	ENST00000396423.4	c.627A>C	p.Glu209Asp	missense_variant	5/10	1	NM_004133.5
HNF4G	ENST00000354370.5	c.486A>C	p.Glu162Asp	missense_variant	6/11	1		P1
HNF4G	ENST00000674002.1	c.597A>C	p.Glu199Asp	missense_variant	5/10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Apr 07, 2023

The c.597A>C (p.E199D) alteration is located in exon 5 (coding exon 5) of the HNF4G gene. This alteration results from a A to C substitution at nucleotide position 597, causing the glutamic acid (E) at amino acid position 199 to be replaced by an aspartic acid (D). 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	0.083
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	14
Dann	Uncertain	0.97
DEOGEN2	Uncertain	0.75	D;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Uncertain	-0.095	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.31
Sift	Benign	0.19	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.0020	B;.
Vest4		0.20
MutPred		0.49		Gain of relative solvent accessibility (P = 0.1684);.;
MVP		0.70
MPC		0.17
ClinPred		0.31	T
GERP RS		2.4
Varity_R		0.23
gMVP		0.32

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

Other links and lift over

dbSNP: rs887807990; hg19: chr8-76465414;