Genetic Variant RNF8:c.1038+17A>G (chr6-37371591-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_003958.4(RNF8):c.1038+17A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 1,608,972 control chromosomes in the GnomAD database, including 164 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 0.011 ( 9 hom., cov: 32)

Exomes 𝑓: 0.013 ( 155 hom. )

Consequence

RNF8
NM_003958.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.388

Publications

4 publications found

Variant links:

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]

RNF8 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0108 (1647/152226) while in subpopulation NFE AF = 0.0162 (1099/68012). AF 95% confidence interval is 0.0154. There are 9 homozygotes in GnomAd4. There are 777 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 gene

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RNF8	NM_003958.4	MANE Select	c.1038+17A>G	intron	N/A	NP_003949.1	O76064-1
RNF8	NM_183078.3		c.1038+17A>G	intron	N/A	NP_898901.1	O76064-3
RNF8	NR_046399.2		n.1326+17A>G	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RNF8	ENST00000373479.9	TSL:1 MANE Select	c.1038+17A>G	intron	N/A	ENSP00000362578.4	O76064-1
RNF8	ENST00000952612.1		c.1038+17A>G	intron	N/A	ENSP00000622671.1
RNF8	ENST00000952613.1		c.1038+17A>G	intron	N/A	ENSP00000622672.1

Frequencies

GnomAD3 genomes

AF:

0.0108

AC:

1648

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00208

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00884

Gnomad ASJ

AF:

0.0150

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0228

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0162

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.0112

AC:

2809

AN:

250936

AF XY:

0.0110

show subpopulations

Gnomad AFR exome

AF:

0.00222

Gnomad AMR exome

AF:

0.00635

Gnomad ASJ exome

AF:

0.0152

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.0252

Gnomad NFE exome

AF:

0.0151

Gnomad OTH exome

AF:

0.0124

GnomAD4 exome

AF:

0.0129

AC:

18811

AN:

1456746

Hom.:

155

Cov.:

AF XY:

0.0127

AC XY:

9230

AN XY:

725080

show subpopulations

African (AFR)

AF:

0.00219

AC:

AN:

33380

American (AMR)

AF:

0.00649

AC:

290

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.0146

AC:

381

AN:

26096

East Asian (EAS)

AF:

0.000176

AC:

AN:

39670

South Asian (SAS)

AF:

0.00212

AC:

183

AN:

86128

European-Finnish (FIN)

AF:

0.0227

AC:

1213

AN:

53370

Middle Eastern (MID)

AF:

0.00249

AC:

AN:

5630

European-Non Finnish (NFE)

AF:

0.0144

AC:

15995

AN:

1107542

Other (OTH)

AF:

0.0109

AC:

655

AN:

60234

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

835

1670

2504

3339

4174

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

554

1108

1662

2216

2770

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0108

AC:

1647

AN:

152226

Hom.:

Cov.:

AF XY:

0.0104

AC XY:

777

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.00205

AC:

AN:

41542

American (AMR)

AF:

0.00883

AC:

135

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0150

AC:

AN:

3466

East Asian (EAS)

AF:

0.000385

AC:

AN:

5190

South Asian (SAS)

AF:

0.00166

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0228

AC:

241

AN:

10580

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0162

AC:

1099

AN:

68012

Other (OTH)

AF:

0.0114

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

170

255

340

425

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0153

Hom.:

Bravo

AF:

0.00885

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.54

(source)

DANN

Benign

0.49

PhyloP100

-0.39

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over