6-37369084-A-G

Position:

• chr6-37369084-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003958.4(RNF8):​c.841A>G​(p.Asn281Asp) 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: RNF8 NM_003958.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.973

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.048478097).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF8	NM_003958.4	c.841A>G	p.Asn281Asp	missense_variant	3/8	ENST00000373479.9	NP_003949.1
RNF8	NM_183078.3	c.841A>G	p.Asn281Asp	missense_variant	3/7		NP_898901.1
RNF8	NR_046399.2	n.1129A>G		non_coding_transcript_exon_variant	3/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF8	ENST00000373479.9	c.841A>G	p.Asn281Asp	missense_variant	3/8	1	NM_003958.4	ENSP00000362578	P1

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

Jun 03, 2024

The c.841A>G (p.N281D) alteration is located in exon 3 (coding exon 3) of the RNF8 gene. This alteration results from a A to G substitution at nucleotide position 841, causing the asparagine (N) at amino acid position 281 to be replaced by an aspartic acid (D). 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	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	9.5
DANN	Benign	0.82
DEOGEN2	Benign	0.073	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.56	T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.048	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.020	N;N
REVEL	Benign	0.12
Sift	Benign	0.69	T;T
Sift4G	Benign	0.63	T;T
Polyphen		0.0	B;.
Vest4		0.13
MutPred		0.15		Gain of ubiquitination at K283 (P = 0.0338);Gain of ubiquitination at K283 (P = 0.0338);
MVP		0.64
MPC		0.51
ClinPred		0.044	T
GERP RS		-0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.048
gMVP		0.15

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-37336860;