4-2512566-A-C

Position:

• chr4-2512566-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.343A>C​(p.Asn115His) 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.610

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]

ENSG00000290180 (HGNC:):

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=0.09303334).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF4	NM_002938.5	c.343A>C	p.Asn115His	missense_variant	6/8	ENST00000314289.13	NP_002929.1
RNF4	NM_001185009.3	c.343A>C	p.Asn115His	missense_variant	7/9		NP_001171938.1
RNF4	XM_047416062.1	c.343A>C	p.Asn115His	missense_variant	7/9		XP_047272018.1
RNF4	NM_001185010.3	c.215-517A>C		intron_variant			NP_001171939.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF4	ENST00000314289.13	c.343A>C	p.Asn115His	missense_variant	6/8	1	NM_002938.5	ENSP00000315212.8
ENSG00000290180	ENST00000703446.1	n.88A>C		non_coding_transcript_exon_variant	1/5			ENSP00000515299.1

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

Nov 03, 2022

The c.343A>C (p.N115H) alteration is located in exon 7 (coding exon 5) of the RNF4 gene. This alteration results from a A to C substitution at nucleotide position 343, causing the asparagine (N) at amino acid position 115 to be replaced by a histidine (H). 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	0.076
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	10
DANN	Benign	0.96
DEOGEN2	Benign	0.23	T;T;T;T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.65	.;T;.;T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.093	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;.;L;L
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.7	N;N;N;N
REVEL	Benign	0.044
Sift	Uncertain	0.022	D;D;D;D
Sift4G	Uncertain	0.057	T;T;T;T
Polyphen		0.67	P;.;P;P
Vest4		0.19
MutPred		0.16		Loss of glycosylation at T110 (P = 0.034);Loss of glycosylation at T110 (P = 0.034);Loss of glycosylation at T110 (P = 0.034);Loss of glycosylation at T110 (P = 0.034);
MVP		0.62
MPC		0.50
ClinPred		0.12	T
GERP RS		-2.3
Varity_R		0.11
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr4-2514293;