Variant 6-37381241-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_003958.4(RNF8):c.1328A>T(p.Asp443Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RNF8
NM_003958.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.45

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 made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a mutagenesis_site Does not affect the monomeric structure but abolishes ability to monoubiquitinate H2A in nucleosomes. (size 0) in uniprot entity RNF8_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21329942).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RNF8	NM_003958.4 linkuse as main transcript	c.1328A>T	p.Asp443Val	missense_variant	7/8	ENST00000373479.9	NP_003949.1
RNF8	NM_183078.3 linkuse as main transcript	c.1236+4208A>T		intron_variant			NP_898901.1
RNF8	NR_046399.2 linkuse as main transcript	n.1616A>T		non_coding_transcript_exon_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF8	ENST00000373479.9 linkuse as main transcript	c.1328A>T	p.Asp443Val	missense_variant	7/8	1	NM_003958.4	ENSP00000362578	P1	O76064-1
RNF8	ENST00000469731.5 linkuse as main transcript	c.1236+4208A>T		intron_variant		5		ENSP00000418879		O76064-3
RNF8	ENST00000498460.1 linkuse as main transcript	c.514+4208A>T		intron_variant		3		ENSP00000417599
RNF8	ENST00000229866.10 linkuse as main transcript	c.*1137A>T		3_prime_UTR_variant, NMD_transcript_variant	7/8	2		ENSP00000229866		O76064-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461840

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2021

The c.1328A>T (p.D443V) alteration is located in exon 7 (coding exon 7) of the RNF8 gene. This alteration results from a A to T substitution at nucleotide position 1328, causing the aspartic acid (D) at amino acid position 443 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.0087

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.11

Eigen

Benign

0.024

Eigen_PC

Benign

0.091

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.80

M_CAP

Benign

0.075

MetaRNN

Benign

0.21

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.6

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.31

PROVEAN

Benign

-2.1

REVEL

Benign

0.18

Sift

Benign

0.28

Sift4G

Benign

0.24

Polyphen

0.64

Vest4

0.28

MutPred

0.46

Gain of MoRF binding (P = 0.0256);

MVP

0.66

MPC

1.5

ClinPred

0.82

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.63

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over