6-37354031-C-T

Variant names:

• chr6-37354031-C-T
• rs195420
• NM_003958.4:c.-134C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003958.4(RNF8):​c.-134C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000507 in 789,350 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000047 (0 hom.)
• Consequence: RNF8 NM_003958.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.540
• Publications: 11 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003958.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF8	NM_003958.4	MANE Select	c.-134C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	NP_003949.1	O76064-1
	RNF8	NM_003958.4	MANE Select	c.-134C>T		5_prime_UTR	Exon 1 of 8	NP_003949.1	O76064-1
	RNF8	NM_183078.3		c.-134C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_898901.1	O76064-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF8	ENST00000373479.9	TSL:1 MANE Select	c.-134C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	ENSP00000362578.4	O76064-1
	RNF8	ENST00000373479.9	TSL:1 MANE Select	c.-134C>T		5_prime_UTR	Exon 1 of 8	ENSP00000362578.4	O76064-1
	RNF8	ENST00000918865.1		c.-134C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	ENSP00000588924.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000471 AC: 3 AN: 637198 Hom.: 0 Cov.: 9 AF XY: 0.00000605 AC XY: 2 AN XY: 330798

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 15974

American (AMR) AF: 0.00 AC: 0 AN: 29208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17496

East Asian (EAS) AF: 0.0000333 AC: 1 AN: 30012

South Asian (SAS) AF: 0.00 AC: 0 AN: 58728

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38998

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2750

European-Non Finnish (NFE) AF: 0.00000486 AC: 2 AN: 411672

Other (OTH) AF: 0.00 AC: 0 AN: 32360

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00462622), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74342

African (AFR) AF: 0.00 AC: 0 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 144

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	7.0
DANN	Benign	0.90
PhyloP100		-0.54
PromoterAI		-0.21	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs195420; hg19: chr6-37321807;