4-2512519-A-T

Position:

• chr4-2512519-A-T

Variant summary

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

The NM_002938.5(RNF4):​c.296A>T​(p.Glu99Val) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RNF4 NM_002938.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.90

Genes affected

RNF4 (HGNC:10067): (ring finger protein 4) The protein encoded by this gene contains a RING finger motif and acts as a transcription regulator. This protein has been shown to interact with, and inhibit the activity of, TRPS1, a transcription suppressor of GATA-mediated transcription. Transcription repressor ZNF278/PATZ is found to interact with this protein, and thus reduce the enhancement of androgen receptor-dependent transcription mediated by this protein. Studies of the mouse and rat counterparts suggested a role of this protein in spermatogenesis. A pseudogene of this gene is found on chromosome 1.[provided by RefSeq, Jul 2010]

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=0.21844083).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNF4	NM_002938.5	c.296A>T	p.Glu99Val	missense_variant	6/8	ENST00000314289.13
RNF4	NM_001185009.3	c.296A>T	p.Glu99Val	missense_variant	7/9
RNF4	XM_047416062.1	c.296A>T	p.Glu99Val	missense_variant	7/9
RNF4	NM_001185010.3	c.214+554A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNF4	ENST00000314289.13	c.296A>T	p.Glu99Val	missense_variant	6/8	1	NM_002938.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Jul 14, 2023

The c.296A>T (p.E99V) alteration is located in exon 7 (coding exon 5) of the RNF4 gene. This alteration results from a A to T substitution at nucleotide position 296, causing the glutamic acid (E) at amino acid position 99 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	0.19
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T;T;T;T
Eigen	Benign	-0.041
Eigen_PC	Benign	0.057
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.4	M;.;M;M
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.2	D;D;D;D
REVEL	Benign	0.076
Sift	Uncertain	0.026	D;D;D;D
Sift4G	Uncertain	0.058	T;T;T;T
Polyphen		0.038	B;.;B;B
Vest4		0.34
MutPred		0.26		Loss of sheet (P = 0.0054);Loss of sheet (P = 0.0054);Loss of sheet (P = 0.0054);Loss of sheet (P = 0.0054);
MVP		0.48
MPC		0.62
ClinPred		0.92	D
GERP RS		4.7
Varity_R		0.19
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: chr4-2514246;