4-2497103-A-G

Variant names:

• chr4-2497103-A-G
• rs1025686608
• NM_002938.5:c.106A>G

Variant summary

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

The NM_002938.5(RNF4):​c.106A>G​(p.Ile36Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000893 in 1,455,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: RNF4 NM_002938.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.74

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=0.15854049).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF4	NM_002938.5	c.106A>G	p.Ile36Val	missense_variant	Exon 3 of 8	ENST00000314289.13	NP_002929.1
RNF4	NM_001185009.3	c.106A>G	p.Ile36Val	missense_variant	Exon 4 of 9		NP_001171938.1
RNF4	NM_001185010.3	c.106A>G	p.Ile36Val	missense_variant	Exon 3 of 7		NP_001171939.1
RNF4	XM_047416062.1	c.106A>G	p.Ile36Val	missense_variant	Exon 4 of 9		XP_047272018.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF4	ENST00000314289.13	c.106A>G	p.Ile36Val	missense_variant	Exon 3 of 8	1	NM_002938.5	ENSP00000315212.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000893 AC: 13 AN: 1455798 Hom.: 0 Cov.: 30 AF XY: 0.00000553 AC XY: 4 AN XY: 723424

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000992

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.106A>G (p.I36V) alteration is located in exon 4 (coding exon 2) of the RNF4 gene. This alteration results from a A to G substitution at nucleotide position 106, causing the isoleucine (I) at amino acid position 36 to be replaced by a valine (V). 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	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	.;T;.;T;.;.;.;T;T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.022
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.78	T;.;T;T;T;T;.;.;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.16	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.8	.;L;L;.;.;.;L;L;L;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.87	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.070
Sift	Benign	0.036	D;D;D;D;D;D;D;D;D;T
Sift4G	Benign	0.091	T;T;T;T;T;T;T;T;T;T
Polyphen		0.023, 0.081	.;B;.;.;.;B;.;B;B;.
Vest4		0.41, 0.41, 0.43, 0.41
MutPred		0.27		Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);
MVP		0.35
MPC		0.42
ClinPred		0.70	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.061
gMVP		0.19

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: rs1025686608; hg19: chr4-2498830;