4-2497067-A-C

Variant names:

• chr4-2497067-A-C
• rs368998654
• NM_002938.5:c.70A>C

Variant summary

Our verdict is Uncertain significance. The variant received 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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T24A) has been classified as Likely benign.

• 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08112016).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002938.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF4	NM_002938.5	MANE Select	c.70A>C	p.Thr24Pro	missense	Exon 3 of 8	NP_002929.1	P78317-1
	RNF4	NM_001185009.3		c.70A>C	p.Thr24Pro	missense	Exon 4 of 9	NP_001171938.1	P78317-1
	RNF4	NM_001185010.3		c.70A>C	p.Thr24Pro	missense	Exon 3 of 7	NP_001171939.1	P78317-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF4	ENST00000314289.13	TSL:1 MANE Select	c.70A>C	p.Thr24Pro	missense	Exon 3 of 8	ENSP00000315212.8	P78317-1
	RNF4	ENST00000506706.5	TSL:1	c.70A>C	p.Thr24Pro	missense	Exon 4 of 9	ENSP00000424076.1	P78317-1
	RNF4	ENST00000511859.5	TSL:1	c.70A>C	p.Thr24Pro	missense	Exon 3 of 7	ENSP00000426615.1	P78317-2

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

African (AFR) AF: 0.0000485 AC: 2 AN: 41266

American (AMR) AF: 0.00 AC: 0 AN: 15204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67960

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.081	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.069
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.048
Sift	Benign	0.25	T
Sift4G	Benign	0.26	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.21		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
Mutation Taster		=89/11	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

Other links and lift over

dbSNP: rs368998654; hg19: chr4-2498794;