4-2497067-A-C

Position:

• chr4-2497067-A-C

Variant summary

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

The NM_002938.5(RNF4):​c.70A>C​(p.Thr24Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 151,766 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: RNF4 NM_002938.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0690

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=0.08112016).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNF4	NM_002938.5	c.70A>C	p.Thr24Pro	missense_variant	3/8	ENST00000314289.13
RNF4	NM_001185009.3	c.70A>C	p.Thr24Pro	missense_variant	4/9
RNF4	NM_001185010.3	c.70A>C	p.Thr24Pro	missense_variant	3/7
RNF4	XM_047416062.1	c.70A>C	p.Thr24Pro	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNF4	ENST00000314289.13	c.70A>C	p.Thr24Pro	missense_variant	3/8	1	NM_002938.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151766 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151766 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74096

Gnomad4 AFR AF: 0.0000485

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

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 04, 2023

The c.70A>C (p.T24P) alteration is located in exon 4 (coding exon 2) of the RNF4 gene. This alteration results from a A to C substitution at nucleotide position 70, causing the threonine (T) at amino acid position 24 to be replaced by a proline (P). 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	0.064
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	2.3
DANN	Benign	0.80
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.48	T;.;T;T;T;T;.;.;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.081	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.048
Sift	Benign	0.25	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.26	T;T;T;T;T;T;T;T;T;T
Polyphen		0.0, 0.0020	.;B;.;.;.;B;.;B;B;.
Vest4		0.12, 0.094, 0.12, 0.12
MutPred		0.21		Gain of glycosylation at T20 (P = 0.0042);Gain of glycosylation at T20 (P = 0.0042);Gain of glycosylation at T20 (P = 0.0042);Gain of glycosylation at T20 (P = 0.0042);Gain of glycosylation at T20 (P = 0.0042);Gain of glycosylation at T20 (P = 0.0042);Gain of glycosylation at T20 (P = 0.0042);Gain of glycosylation at T20 (P = 0.0042);Gain of glycosylation at T20 (P = 0.0042);Gain of glycosylation at T20 (P = 0.0042);
MVP		0.56
MPC		0.63
ClinPred		0.033	T
GERP RS		-0.85
Varity_R		0.058
gMVP		0.14

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: rs368998654; hg19: chr4-2498794;