NM_003958.4:c.240+8A>G

Variant names:

• chr6-37360582-A-G
• rs370830769
• NM_003958.4:c.240+8A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_003958.4(RNF8):​c.240+8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000317 in 1,610,674 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: RNF8 NM_003958.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001789
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.993
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 6-37360582-A-G is Benign according to our data. Variant chr6-37360582-A-G is described in ClinVar as [Benign]. Clinvar id is 780620.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF8	NM_003958.4	c.240+8A>G		splice_region_variant, intron_variant	Intron 2 of 7	ENST00000373479.9	NP_003949.1
RNF8	NM_183078.3	c.240+8A>G		splice_region_variant, intron_variant	Intron 2 of 6		NP_898901.1
RNF8	NR_046399.2	n.422+8A>G		splice_region_variant, intron_variant	Intron 2 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF8	ENST00000373479.9	c.240+8A>G		splice_region_variant, intron_variant	Intron 2 of 7	1	NM_003958.4	ENSP00000362578.4

Frequencies

GnomAD3 genomes AF: 0.00191 AC: 291 AN: 152084 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00657

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000514 AC: 128 AN: 249266 AF XY: 0.000305

Gnomad AFR exome AF: 0.00648

Gnomad AMR exome AF: 0.000583

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000149 AC: 218 AN: 1458474 Hom.: 1 Cov.: 31 AF XY: 0.000126 AC XY: 91 AN XY: 725078

African (AFR) AF: 0.00512 AC: 171 AN: 33408

American (AMR) AF: 0.000516 AC: 23 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.0000584 AC: 5 AN: 85624

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1109804

Other (OTH) AF: 0.000266 AC: 16 AN: 60250

GnomAD4 genome AF: 0.00192 AC: 292 AN: 152200 Hom.: 2 Cov.: 32 AF XY: 0.00187 AC XY: 139 AN XY: 74434

African (AFR) AF: 0.00658 AC: 273 AN: 41518

American (AMR) AF: 0.00105 AC: 16 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.00104 Hom.: 0

Bravo AF: 0.00220

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 10, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	5.8
DANN	Benign	0.89
PhyloP100		0.99
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00018
dbscSNV1_RF	Benign	0.0040
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: rs370830769; hg19: chr6-37328358;