chr6-37381144-C-G

Variant names:

• chr6-37381144-C-G
• rs2284923
• NM_003958.4:c.1237-6C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003958.4(RNF8):​c.1237-6C>G variant causes a splice region, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RNF8 NM_003958.4 splice_region, intron
• Scores: Splicing: ADA: 0.9981
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.247
• Publications: 38 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF8	NM_003958.4	c.1237-6C>G		splice_region_variant, intron_variant	Intron 6 of 7	ENST00000373479.9	NP_003949.1
RNF8	NM_183078.3	c.1236+4111C>G		intron_variant	Intron 6 of 6		NP_898901.1
RNF8	NR_046399.2	n.1525-6C>G		splice_region_variant, intron_variant	Intron 6 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF8	ENST00000373479.9	c.1237-6C>G		splice_region_variant, intron_variant	Intron 6 of 7	1	NM_003958.4	ENSP00000362578.4
RNF8	ENST00000469731.5	c.1236+4111C>G		intron_variant	Intron 6 of 6	5		ENSP00000418879.1
RNF8	ENST00000498460.1	c.513+4111C>G		intron_variant	Intron 3 of 3	3		ENSP00000417599.1
RNF8	ENST00000229866.10	n.*1046-6C>G		splice_region_variant, intron_variant	Intron 6 of 7	2		ENSP00000229866.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 86400

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	14
DANN	Benign	0.55
PhyloP100		-0.25
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		0.60		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.30		Position offset: 1
DS_AL_spliceai		0.60		Position offset: 6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2284923; hg19: chr6-37348920;