6-37368731-G-T

Variant names:

• chr6-37368731-G-T
• NM_003958.4:c.488G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003958.4(RNF8):​c.488G>T​(p.Gly163Val) 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. 14/22 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: RNF8 NM_003958.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.45
• Publications: 0 publications found

Genes affected

RNF8 (HGNC:10071): (ring finger protein 8) The protein encoded by this gene contains a RING finger motif and an FHA domain. This protein has been shown to interact with several class II ubiquitin-conjugating enzymes (E2), including UBE2E1/UBCH6, UBE2E2, and UBE2E3, and may act as an ubiquitin ligase (E3) in the ubiquitination of certain nuclear proteins. This protein is also known to play a role in the DNA damage response and depletion of this protein causes cell growth inhibition and cell cycle arrest. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]

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=0.094043225).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF8	NM_003958.4	c.488G>T	p.Gly163Val	missense_variant	Exon 3 of 8	ENST00000373479.9	NP_003949.1
RNF8	NM_183078.3	c.488G>T	p.Gly163Val	missense_variant	Exon 3 of 7		NP_898901.1
RNF8	NR_046399.2	n.776G>T		non_coding_transcript_exon_variant	Exon 3 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF8	ENST00000373479.9	c.488G>T	p.Gly163Val	missense_variant	Exon 3 of 8	1	NM_003958.4	ENSP00000362578.4

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

Mar 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.488G>T (p.G163V) alteration is located in exon 3 (coding exon 3) of the RNF8 gene. This alteration results from a G to T substitution at nucleotide position 488, causing the glycine (G) at amino acid position 163 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	0.074
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	14
DANN	Benign	0.94
DEOGEN2	Benign	0.11	T;.;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.094	T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.1	M;.;M
PhyloP100		1.4
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.83	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.073	T;D;D
Sift4G	Benign	0.13	T;T;T
Polyphen		0.011	B;B;.
Vest4		0.14
MutPred		0.11		Loss of catalytic residue at G163 (P = 0.0969);.;Loss of catalytic residue at G163 (P = 0.0969);
MVP		0.73
MPC		0.59
ClinPred		0.064	T
GERP RS		1.8
PromoterAI		0.068	Neutral
Varity_R		0.063
gMVP		0.20
Mutation Taster		=88/12	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

hg19: chr6-37336507;