rs2284922

Positions:

• chr6-37381257-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_003958.4(RNF8):​c.1344G>A​(p.Thr448=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.382 in 1,613,596 control chromosomes in the GnomAD database, including 126,926 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.43 (14981 hom., cov: 32)
  • Exomes 𝑓: 0.38 (111945 hom.)
• Consequence: RNF8 NM_003958.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.954

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP7: Synonymous conserved (PhyloP=-0.954 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.72 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNF8	NM_003958.4	c.1344G>A	p.Thr448=	synonymous_variant	7/8	ENST00000373479.9
RNF8	NM_183078.3	c.1236+4224G>A		intron_variant
RNF8	NR_046399.2	n.1632G>A		non_coding_transcript_exon_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNF8	ENST00000373479.9	c.1344G>A	p.Thr448=	synonymous_variant	7/8	1	NM_003958.4	P1
RNF8	ENST00000469731.5	c.1236+4224G>A		intron_variant		5
RNF8	ENST00000498460.1	c.514+4224G>A		intron_variant		3
RNF8	ENST00000229866.10	c.*1153G>A		3_prime_UTR_variant, NMD_transcript_variant	7/8	2

Frequencies

GnomAD3 genomes AF: 0.428 AC: 65060 AN: 151844 Hom.: 14947 Cov.: 32

Gnomad AFR AF: 0.531

Gnomad AMI AF: 0.217

Gnomad AMR AF: 0.485

Gnomad ASJ AF: 0.433

Gnomad EAS AF: 0.740

Gnomad SAS AF: 0.603

Gnomad FIN AF: 0.287

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.451

GnomAD3 exomes AF: 0.441 AC: 110920 AN: 251466 Hom.: 26856 AF XY: 0.439 AC XY: 59681 AN XY: 135906

Gnomad AFR exome AF: 0.533

Gnomad AMR exome AF: 0.538

Gnomad ASJ exome AF: 0.435

Gnomad EAS exome AF: 0.743

Gnomad SAS exome AF: 0.587

Gnomad FIN exome AF: 0.290

Gnomad NFE exome AF: 0.342

Gnomad OTH exome AF: 0.408

GnomAD4 exome AF: 0.377 AC: 551012 AN: 1461634 Hom.: 111945 Cov.: 38 AF XY: 0.382 AC XY: 278030 AN XY: 727126

Gnomad4 AFR exome AF: 0.540

Gnomad4 AMR exome AF: 0.529

Gnomad4 ASJ exome AF: 0.429

Gnomad4 EAS exome AF: 0.768

Gnomad4 SAS exome AF: 0.584

Gnomad4 FIN exome AF: 0.286

Gnomad4 NFE exome AF: 0.337

Gnomad4 OTH exome AF: 0.407

GnomAD4 genome AF: 0.429 AC: 65155 AN: 151962 Hom.: 14981 Cov.: 32 AF XY: 0.434 AC XY: 32242 AN XY: 74252

Gnomad4 AFR AF: 0.532

Gnomad4 AMR AF: 0.485

Gnomad4 ASJ AF: 0.433

Gnomad4 EAS AF: 0.739

Gnomad4 SAS AF: 0.603

Gnomad4 FIN AF: 0.287

Gnomad4 NFE AF: 0.341

Gnomad4 OTH AF: 0.457

Alfa AF: 0.370 Hom.: 17450

Bravo AF: 0.446

Asia WGS AF: 0.660 AC: 2297 AN: 3478

EpiCase AF: 0.344

EpiControl AF: 0.348

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.6
DANN	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.4

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: rs2284922; hg19: chr6-37349033; COSMIC: COSV104567136;