NM_003958.4:c.1377G>A

Variant names:

• chr6-37381290-G-A
• rs34150698
• NM_003958.4:c.1377G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.333
• Publications: 11 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 -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.

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.1377G>A	p.Lys459Lys	synonymous	Exon 7 of 8	NP_003949.1	O76064-1
	RNF8	NM_183078.3		c.1236+4257G>A		intron	N/A	NP_898901.1	O76064-3
	RNF8	NR_046399.2		n.1665G>A		non_coding_transcript_exon	Exon 7 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF8	ENST00000373479.9	TSL:1 MANE Select	c.1377G>A	p.Lys459Lys	synonymous	Exon 7 of 8	ENSP00000362578.4	O76064-1
	RNF8	ENST00000952612.1		c.1377G>A	p.Lys459Lys	synonymous	Exon 7 of 9	ENSP00000622671.1
	RNF8	ENST00000952613.1		c.1377G>A	p.Lys459Lys	synonymous	Exon 7 of 9	ENSP00000622672.1

Frequencies

GnomAD3 genomes AF: 0.0559 AC: 8509 AN: 152164 Hom.: 330 Cov.: 32

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

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.: 34 AF XY: 0.0666 AC XY: 48467 AN XY: 727198

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: 16 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

GnomAD4 genome AF: 0.0559 AC: 8510 AN: 152282 Hom.: 330 Cov.: 32 AF XY: 0.0576 AC XY: 4290 AN XY: 74460

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: 7 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: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0755 AC: 5137 AN: 68020

Other (OTH) AF: 0.0587 AC: 124 AN: 2114

Alfa AF: 0.0634 Hom.: 367

Bravo AF: 0.0498

Asia WGS AF: 0.0130 AC: 45 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	5.8
DANN	Benign	0.59
PhyloP100		0.33
Mutation Taster		=91/9	polymorphism (auto)

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

Other links and lift over

dbSNP: rs34150698; hg19: chr6-37349066;