4-2512457-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002938.5(RNF4):c.234G>T(p.Arg78Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000391 in 1,612,320 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000039 ( 1 hom. )

Consequence

RNF4
NM_002938.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.824

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 was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14425924).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
RNF4	NM_002938.5 link	c.234G>T	p.Arg78Ser	missense_variant	Exon 6 of 8	ENST00000314289.13	NP_002929.1
RNF4	NM_001185009.3 link	c.234G>T	p.Arg78Ser	missense_variant	Exon 7 of 9		NP_001171938.1
RNF4	XM_047416062.1 link	c.234G>T	p.Arg78Ser	missense_variant	Exon 7 of 9		XP_047272018.1
RNF4	NM_001185010.3 link	c.214+492G>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.234G>T	p.Arg78Ser	missense_variant	Exon 6 of 8	1	NM_002938.5	ENSP00000315212.8		P78317-1
ENSG00000290180	ENST00000703446.1 link	n.-22G>T		upstream_gene_variant				ENSP00000515299.1		H0YAI5

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000203

AC:

AN:

246050

AF XY:

0.0000300

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000449

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000390

AC:

AN:

1460076

Hom.:

Cov.:

AF XY:

0.0000317

AC XY:

AN XY:

726190

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

AC:

AN:

33446

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

44384

Gnomad4 ASJ exome

AF:

0.0000384

AC:

AN:

26070

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39664

Gnomad4 SAS exome

AF:

0.0000465

AC:

AN:

85986

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53290

Gnomad4 NFE exome

AF:

0.0000315

AC:

AN:

1111158

Gnomad4 Remaining exome

AF:

0.0000829

AC:

AN:

60312

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.0000481

AC:

0.0000481394

AN:

0.0000481394

Gnomad4 AMR

AF:

0.0000654

AC:

0.0000654108

AN:

0.0000654108

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000441

AC:

0.0000441138

AN:

0.0000441138

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000521

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.000238

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000826

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 13, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.234G>T (p.R78S) alteration is located in exon 7 (coding exon 5) of the RNF4 gene. This alteration results from a G to T substitution at nucleotide position 234, causing the arginine (R) at amino acid position 78 to be replaced by a serine (S). 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

Uncertain

0.45

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.12

T;T;T;T

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.33

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.69

.;T;.;T

M_CAP

Benign

0.026

MetaRNN

Benign

0.14

T;T;T;T

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.7

L;.;L;L

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.1

N;N;N;N

REVEL

Benign

0.23

Sift

Benign

0.21

T;T;T;T

Sift4G

Benign

0.53

T;T;T;T

Polyphen

0.96

D;.;D;D

Vest4

0.61

MutPred

0.35

Loss of glycosylation at P76 (P = 0.0075);Loss of glycosylation at P76 (P = 0.0075);Loss of glycosylation at P76 (P = 0.0075);Loss of glycosylation at P76 (P = 0.0075);

MVP

0.77

MPC

0.56

ClinPred

0.23

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.21

gMVP

0.49

Mutation Taster

=65/35

polymorphism

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over