6-37381241-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.45

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

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
RNF8	NM_003958.4	c.1328A>T	p.Asp443Val	missense_variant	7/8	ENST00000373479.9
RNF8	NM_183078.3	c.1236+4208A>T		intron_variant
RNF8	NR_046399.2	n.1616A>T		non_coding_transcript_exon_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNF8	ENST00000373479.9	c.1328A>T	p.Asp443Val	missense_variant	7/8	1	NM_003958.4	P1
RNF8	ENST00000469731.5	c.1236+4208A>T		intron_variant		5
RNF8	ENST00000498460.1	c.514+4208A>T		intron_variant		3
RNF8	ENST00000229866.10	c.*1137A>T		3_prime_UTR_variant, NMD_transcript_variant	7/8	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

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

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	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;