6-37371591-A-G

Variant names:

• chr6-37371591-A-G
• rs77440008
• NM_003958.4:c.1038+17A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.388
• Publications: 4 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=-0.89).
• 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF8	NM_003958.4	c.1038+17A>G		intron_variant	Intron 4 of 7	ENST00000373479.9	NP_003949.1
RNF8	NM_183078.3	c.1038+17A>G		intron_variant	Intron 4 of 6		NP_898901.1
RNF8	NR_046399.2	n.1326+17A>G		intron_variant	Intron 4 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF8	ENST00000373479.9	c.1038+17A>G		intron_variant	Intron 4 of 7	1	NM_003958.4	ENSP00000362578.4
RNF8	ENST00000469731.5	c.1038+17A>G		intron_variant	Intron 4 of 6	5		ENSP00000418879.1
RNF8	ENST00000498460.1	c.405+17A>G		intron_variant	Intron 2 of 3	3		ENSP00000417599.1
RNF8	ENST00000229866.10	n.*847+17A>G		intron_variant	Intron 4 of 7	2		ENSP00000229866.6

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1648 AN: 152108 Hom.: 9 Cov.: 32

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

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.: 28 AF XY: 0.0127 AC XY: 9230 AN XY: 725080

African (AFR) AF: 0.00219 AC: 73 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: 7 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: 14 AN: 5630

European-Non Finnish (NFE) AF: 0.0144 AC: 15995 AN: 1107542

Other (OTH) AF: 0.0109 AC: 655 AN: 60234

GnomAD4 genome AF: 0.0108 AC: 1647 AN: 152226 Hom.: 9 Cov.: 32 AF XY: 0.0104 AC XY: 777 AN XY: 74418

African (AFR) AF: 0.00205 AC: 85 AN: 41542

American (AMR) AF: 0.00883 AC: 135 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 52 AN: 3466

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4822

European-Finnish (FIN) AF: 0.0228 AC: 241 AN: 10580

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0162 AC: 1099 AN: 68012

Other (OTH) AF: 0.0114 AC: 24 AN: 2112

Alfa AF: 0.0153 Hom.: 5

Bravo AF: 0.00885

Asia WGS AF: 0.00173 AC: 7 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.54
DANN	Benign	0.49
PhyloP100		-0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs77440008; hg19: chr6-37339367;