6-37360553-A-T

Variant names:

• chr6-37360553-A-T
• rs184803752
• NM_003958.4:c.219A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003958.4(RNF8):​c.219A>T​(p.Gln73His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,746 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q73Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: RNF8 NM_003958.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.20
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF8	NM_003958.4	c.219A>T	p.Gln73His	missense_variant	Exon 2 of 8	ENST00000373479.9	NP_003949.1
RNF8	NM_183078.3	c.219A>T	p.Gln73His	missense_variant	Exon 2 of 7		NP_898901.1
RNF8	NR_046399.2	n.401A>T		non_coding_transcript_exon_variant	Exon 2 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF8	ENST00000373479.9	c.219A>T	p.Gln73His	missense_variant	Exon 2 of 8	1	NM_003958.4	ENSP00000362578.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461746 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727176

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111918

Other (OTH) AF: 0.0000166 AC: 1 AN: 60386

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D;.;.
Eigen	Benign	-0.062
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.82	T;D;D
M_CAP	Uncertain	0.097	D
MetaRNN	Uncertain	0.48	T;T;T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	1.7	L;.;L
PhyloP100		1.2
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.4	N;D;N
REVEL	Uncertain	0.52
Sift	Benign	0.088	T;T;T
Sift4G	Uncertain	0.010	D;D;D
Polyphen		0.88	P;D;.
Vest4		0.22
MutPred		0.42		Loss of sheet (P = 0.0025);.;Loss of sheet (P = 0.0025);
MVP		0.85
MPC		1.2
ClinPred		0.94	D
GERP RS		-1.4
Varity_R		0.32
gMVP		0.86
Mutation Taster		=66/34	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: rs184803752; hg19: chr6-37328329;