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6-37381241-A-T

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. 15/20 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

1
18

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]

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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 UniProt
RNF8NM_003958.4 linkuse as main transcriptc.1328A>T p.Asp443Val missense_variant 7/8 ENST00000373479.9
RNF8NM_183078.3 linkuse as main transcriptc.1236+4208A>T intron_variant
RNF8NR_046399.2 linkuse as main transcriptn.1616A>T non_coding_transcript_exon_variant 7/8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RNF8ENST00000373479.9 linkuse as main transcriptc.1328A>T p.Asp443Val missense_variant 7/81 NM_003958.4 P1O76064-1
RNF8ENST00000469731.5 linkuse as main transcriptc.1236+4208A>T intron_variant 5 O76064-3
RNF8ENST00000498460.1 linkuse as main transcriptc.514+4208A>T intron_variant 3
RNF8ENST00000229866.10 linkuse as main transcriptc.*1137A>T 3_prime_UTR_variant, NMD_transcript_variant 7/82 O76064-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461840
Hom.:
0
Cov.:
35
AF XY:
0.00
AC XY:
0
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.:
32

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 submitterclinical testingAmbry GeneticsDec 03, 2021The 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
T
BayesDel_noAF
Benign
-0.25
Cadd
Benign
18
Dann
Benign
0.82
DEOGEN2
Benign
0.11
T
Eigen
Benign
0.024
Eigen_PC
Benign
0.091
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Benign
0.80
T
M_CAP
Benign
0.075
D
MetaRNN
Benign
0.21
T
MetaSVM
Benign
-0.91
T
MutationAssessor
Benign
1.6
L
MutationTaster
Benign
1.0
D;D
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-2.1
N
REVEL
Benign
0.18
Sift
Benign
0.28
T
Sift4G
Benign
0.24
T
Polyphen
0.64
P
Vest4
0.28
MutPred
0.46
Gain of MoRF binding (P = 0.0256);
MVP
0.66
MPC
1.5
ClinPred
0.82
D
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.

Other links and lift over

hg19: chr6-37349017; API