Genetic Variant NM_003958.4:c.1377G>A (chr6-37381290-G-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP7BA1

The NM_003958.4(RNF8):c.1377G>A(p.Lys459Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.066 in 1,614,066 control chromosomes in the GnomAD database, including 4,063 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 0.056 ( 330 hom., cov: 32)

Exomes 𝑓: 0.067 ( 3733 hom. )

Consequence

RNF8
NM_003958.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.333

Publications

11 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 -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP7

Synonymous conserved (PhyloP=0.333 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0738 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF8	NM_003958.4 link	c.1377G>A	p.Lys459Lys	synonymous_variant	Exon 7 of 8	ENST00000373479.9	NP_003949.1	O76064-1
RNF8	NR_046399.2 link	n.1665G>A		non_coding_transcript_exon_variant	Exon 7 of 8
RNF8	NM_183078.3 link	c.1236+4257G>A		intron_variant	Intron 6 of 6		NP_898901.1	O76064-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF8	ENST00000373479.9 link	c.1377G>A	p.Lys459Lys	synonymous_variant	Exon 7 of 8	1	NM_003958.4	ENSP00000362578.4		O76064-1

Frequencies

GnomAD3 genomes

AF:

0.0559

AC:

8509

AN:

152164

Hom.:

330

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0121

Gnomad AMI

AF:

0.0757

Gnomad AMR

AF:

0.0544

Gnomad ASJ

AF:

0.118

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.0243

Gnomad FIN

AF:

0.121

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.0755

Gnomad OTH

AF:

0.0593

GnomAD2 exomes

AF:

0.0628

AC:

15779

AN:

251452

AF XY:

0.0635

show subpopulations

Gnomad AFR exome

AF:

0.0117

Gnomad AMR exome

AF:

0.0396

Gnomad ASJ exome

AF:

0.112

Gnomad EAS exome

AF:

0.000761

Gnomad FIN exome

AF:

0.120

Gnomad NFE exome

AF:

0.0806

Gnomad OTH exome

AF:

0.0701

GnomAD4 exome

AF:

0.0671

AC:

98046

AN:

1461784

Hom.:

3733

Cov.:

AF XY:

0.0666

AC XY:

48467

AN XY:

727198

show subpopulations

African (AFR)

AF:

0.0100

AC:

335

AN:

33480

American (AMR)

AF:

0.0414

AC:

1852

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.113

AC:

2966

AN:

26134

East Asian (EAS)

AF:

0.000403

AC:

AN:

39698

South Asian (SAS)

AF:

0.0302

AC:

2607

AN:

86256

European-Finnish (FIN)

AF:

0.117

AC:

6268

AN:

53418

Middle Eastern (MID)

AF:

0.0652

AC:

376

AN:

5768

European-Non Finnish (NFE)

AF:

0.0718

AC:

79787

AN:

1111910

Other (OTH)

AF:

0.0636

AC:

3839

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

4754

9507

14261

19014

23768

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0559

AC:

8510

AN:

152282

Hom.:

330

Cov.:

AF XY:

0.0576

AC XY:

4290

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0121

AC:

503

AN:

41568

American (AMR)

AF:

0.0543

AC:

831

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.118

AC:

409

AN:

3468

East Asian (EAS)

AF:

0.00135

AC:

AN:

5184

South Asian (SAS)

AF:

0.0247

AC:

119

AN:

4820

European-Finnish (FIN)

AF:

0.121

AC:

1281

AN:

10604

Middle Eastern (MID)

AF:

0.102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0755

AC:

5137

AN:

68020

Other (OTH)

AF:

0.0587

AC:

124

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

422

844

1265

1687

2109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0634

Hom.:

367

Bravo

AF:

0.0498

Asia WGS

AF:

0.0130

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

5.8

(source)

DANN

Benign

0.59

PhyloP100

0.33

Mutation Taster

=91/9

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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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NM_003958.4:c.1377G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over