NM_003958.4:c.1344G>A

Variant names:

• chr6-37381257-G-A
• rs2284922
• NM_003958.4:c.1344G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_003958.4(RNF8):​c.1344G>A​(p.Thr448Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.382 in 1,613,596 control chromosomes in the GnomAD database, including 126,926 homozygotes. 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 0.43 (14981 hom., cov: 32)
  • Exomes 𝑓: 0.38 (111945 hom.)
• Consequence: RNF8 NM_003958.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.954
• Publications: 29 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP7: Synonymous conserved (PhyloP=-0.954 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.72 is higher than 0.05.

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.1344G>A	p.Thr448Thr	synonymous	Exon 7 of 8	NP_003949.1	O76064-1
	RNF8	NM_183078.3		c.1236+4224G>A		intron	N/A	NP_898901.1	O76064-3
	RNF8	NR_046399.2		n.1632G>A		non_coding_transcript_exon	Exon 7 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF8	ENST00000373479.9	TSL:1 MANE Select	c.1344G>A	p.Thr448Thr	synonymous	Exon 7 of 8	ENSP00000362578.4	O76064-1
	RNF8	ENST00000952612.1		c.1344G>A	p.Thr448Thr	synonymous	Exon 7 of 9	ENSP00000622671.1
	RNF8	ENST00000952613.1		c.1344G>A	p.Thr448Thr	synonymous	Exon 7 of 9	ENSP00000622672.1

Frequencies

GnomAD3 genomes AF: 0.428 AC: 65060 AN: 151844 Hom.: 14947 Cov.: 32

Gnomad AFR AF: 0.531

Gnomad AMI AF: 0.217

Gnomad AMR AF: 0.485

Gnomad ASJ AF: 0.433

Gnomad EAS AF: 0.740

Gnomad SAS AF: 0.603

Gnomad FIN AF: 0.287

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.451

GnomAD2 exomes AF: 0.441 AC: 110920 AN: 251466 AF XY: 0.439

Gnomad AFR exome AF: 0.533

Gnomad AMR exome AF: 0.538

Gnomad ASJ exome AF: 0.435

Gnomad EAS exome AF: 0.743

Gnomad FIN exome AF: 0.290

Gnomad NFE exome AF: 0.342

Gnomad OTH exome AF: 0.408

GnomAD4 exome AF: 0.377 AC: 551012 AN: 1461634 Hom.: 111945 Cov.: 38 AF XY: 0.382 AC XY: 278030 AN XY: 727126

African (AFR) AF: 0.540 AC: 18084 AN: 33468

American (AMR) AF: 0.529 AC: 23669 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.429 AC: 11209 AN: 26134

East Asian (EAS) AF: 0.768 AC: 30494 AN: 39698

South Asian (SAS) AF: 0.584 AC: 50388 AN: 86250

European-Finnish (FIN) AF: 0.286 AC: 15299 AN: 53420

Middle Eastern (MID) AF: 0.434 AC: 2501 AN: 5768

European-Non Finnish (NFE) AF: 0.337 AC: 374776 AN: 1111784

Other (OTH) AF: 0.407 AC: 24592 AN: 60390

GnomAD4 genome AF: 0.429 AC: 65155 AN: 151962 Hom.: 14981 Cov.: 32 AF XY: 0.434 AC XY: 32242 AN XY: 74252

African (AFR) AF: 0.532 AC: 22041 AN: 41438

American (AMR) AF: 0.485 AC: 7407 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 1502 AN: 3470

East Asian (EAS) AF: 0.739 AC: 3812 AN: 5156

South Asian (SAS) AF: 0.603 AC: 2907 AN: 4824

European-Finnish (FIN) AF: 0.287 AC: 3025 AN: 10542

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.341 AC: 23173 AN: 67948

Other (OTH) AF: 0.457 AC: 965 AN: 2112

Alfa AF: 0.376 Hom.: 22075

Bravo AF: 0.446

Asia WGS AF: 0.660 AC: 2297 AN: 3478

EpiCase AF: 0.344

EpiControl AF: 0.348

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.6
DANN	Benign	0.58
PhyloP100		-0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs2284922; hg19: chr6-37349033; COSMIC: COSV104567136;