Genetic Variant NM_002938.5:c.365C>T (chr4-2512588-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002938.5(RNF4):c.365C>T(p.Thr122Ile) 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

RNF4
NM_002938.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.78

Variant links:

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]

RNF4 links:

ENSG00000290180 (HGNC:):

ENSG00000290180 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.108380646).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
RNF4	NM_002938.5 link	c.365C>T	p.Thr122Ile	missense_variant	Exon 6 of 8	ENST00000314289.13	NP_002929.1
RNF4	NM_001185009.3 link	c.365C>T	p.Thr122Ile	missense_variant	Exon 7 of 9		NP_001171938.1
RNF4	XM_047416062.1 link	c.365C>T	p.Thr122Ile	missense_variant	Exon 7 of 9		XP_047272018.1
RNF4	NM_001185010.3 link	c.215-495C>T		intron_variant	Intron 5 of 6		NP_001171939.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF4	ENST00000314289.13 link	c.365C>T	p.Thr122Ile	missense_variant	Exon 6 of 8	1	NM_002938.5	ENSP00000315212.8		P78317-1
ENSG00000290180	ENST00000703446.1 link	n.110C>T		non_coding_transcript_exon_variant	Exon 1 of 5			ENSP00000515299.1		H0YAI5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.365C>T (p.T122I) alteration is located in exon 7 (coding exon 5) of the RNF4 gene. This alteration results from a C to T substitution at nucleotide position 365, causing the threonine (T) at amino acid position 122 to be replaced by an isoleucine (I). 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

0.11

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.13

T;T;T;T

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.68

.;T;.;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.11

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.9

L;.;L;L

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.4

N;N;N;N

REVEL

Benign

0.039

Sift

Benign

0.032

D;D;D;D

Sift4G

Benign

0.19

T;T;T;T

Polyphen

0.015

B;.;B;B

Vest4

0.081

MutPred

0.30

Loss of disorder (P = 0.0502);Loss of disorder (P = 0.0502);Loss of disorder (P = 0.0502);Loss of disorder (P = 0.0502);

MVP

0.33

MPC

0.59

ClinPred

0.14

GERP RS

4.5

Varity_R

0.12

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over