6-37381144-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003958.4(RNF8):​c.1237-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.489 in 1,610,168 control chromosomes in the GnomAD database, including 198,017 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.52 (20883 hom., cov: 32)
  • Exomes 𝑓: 0.49 (177134 hom.)
• Consequence: RNF8 NM_003958.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002030
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.746 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003958.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF8	NM_003958.4	MANE Select	c.1237-6C>T		splice_region intron	N/A	NP_003949.1	O76064-1
	RNF8	NM_183078.3		c.1236+4111C>T		intron	N/A	NP_898901.1	O76064-3
	RNF8	NR_046399.2		n.1525-6C>T		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF8	ENST00000373479.9	TSL:1 MANE Select	c.1237-6C>T		splice_region intron	N/A	ENSP00000362578.4	O76064-1
	RNF8	ENST00000952612.1		c.1237-6C>T		splice_region intron	N/A	ENSP00000622671.1
	RNF8	ENST00000952613.1		c.1237-6C>T		splice_region intron	N/A	ENSP00000622672.1

Frequencies

GnomAD3 genomes AF: 0.515 AC: 78298 AN: 151942 Hom.: 20842 Cov.: 32

Gnomad AFR AF: 0.582

Gnomad AMI AF: 0.408

Gnomad AMR AF: 0.544

Gnomad ASJ AF: 0.466

Gnomad EAS AF: 0.766

Gnomad SAS AF: 0.639

Gnomad FIN AF: 0.380

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.466

Gnomad OTH AF: 0.514

GnomAD2 exomes AF: 0.519 AC: 130531 AN: 251296 AF XY: 0.518

Gnomad AFR exome AF: 0.580

Gnomad AMR exome AF: 0.574

Gnomad ASJ exome AF: 0.473

Gnomad EAS exome AF: 0.769

Gnomad FIN exome AF: 0.383

Gnomad NFE exome AF: 0.458

Gnomad OTH exome AF: 0.491

GnomAD4 exome AF: 0.486 AC: 709058 AN: 1458108 Hom.: 177134 Cov.: 33 AF XY: 0.489 AC XY: 355086 AN XY: 725584

African (AFR) AF: 0.583 AC: 19470 AN: 33382

American (AMR) AF: 0.568 AC: 25419 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.468 AC: 12213 AN: 26114

East Asian (EAS) AF: 0.792 AC: 31448 AN: 39686

South Asian (SAS) AF: 0.623 AC: 53691 AN: 86168

European-Finnish (FIN) AF: 0.382 AC: 20389 AN: 53414

Middle Eastern (MID) AF: 0.468 AC: 2697 AN: 5762

European-Non Finnish (NFE) AF: 0.463 AC: 513574 AN: 1108584

Other (OTH) AF: 0.500 AC: 30157 AN: 60284

GnomAD4 genome AF: 0.516 AC: 78391 AN: 152060 Hom.: 20883 Cov.: 32 AF XY: 0.518 AC XY: 38529 AN XY: 74338

African (AFR) AF: 0.582 AC: 24140 AN: 41468

American (AMR) AF: 0.544 AC: 8313 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.466 AC: 1617 AN: 3470

East Asian (EAS) AF: 0.766 AC: 3975 AN: 5190

South Asian (SAS) AF: 0.638 AC: 3078 AN: 4826

European-Finnish (FIN) AF: 0.380 AC: 4015 AN: 10554

Middle Eastern (MID) AF: 0.469 AC: 138 AN: 294

European-Non Finnish (NFE) AF: 0.466 AC: 31650 AN: 67962

Other (OTH) AF: 0.518 AC: 1094 AN: 2112

Alfa AF: 0.485 Hom.: 86400

Bravo AF: 0.529

Asia WGS AF: 0.688 AC: 2394 AN: 3478

EpiCase AF: 0.454

EpiControl AF: 0.458

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.96
DANN	Benign	0.45
PhyloP100		-0.25
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000020
dbscSNV1_RF	Benign	0.0
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

dbSNP: rs2284923; hg19: chr6-37348920; COSMIC: COSV57721165;