NM_015324.4:c.1303C>G

Variant names:

• chr11-6600214-G-C
• rs1202462843
• NM_015324.4:c.1303C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015324.4(RRP8):​c.1303C>G​(p.Pro435Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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: 6.9e-7 (0 hom.)
• Consequence: RRP8 NM_015324.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.88
• Publications: 0 publications found

Genes affected

RRP8 (HGNC:29030): (ribosomal RNA processing 8) Enables methylated histone binding activity. Involved in several processes, including cellular response to glucose starvation; intrinsic apoptotic signaling pathway by p53 class mediator; and regulation of gene expression. Located in several cellular components, including cytosol; nuclear lumen; and rDNA heterochromatin. Part of chromatin silencing complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.094201535).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015324.4. 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
	RRP8	NM_015324.4	MANE Select	c.1303C>G	p.Pro435Ala	missense	Exon 7 of 7	NP_056139.1	O43159

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RRP8	ENST00000254605.11	TSL:1 MANE Select	c.1303C>G	p.Pro435Ala	missense	Exon 7 of 7	ENSP00000254605.6	O43159
	RRP8	ENST00000874194.1		c.1261C>G	p.Pro421Ala	missense	Exon 7 of 7	ENSP00000544253.1
	RRP8	ENST00000534343.1	TSL:2	c.355C>G	p.Pro119Ala	missense	Exon 4 of 4	ENSP00000436960.1	E9PPP6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455204 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 723856

⚠️ 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: 32844

American (AMR) AF: 0.00 AC: 0 AN: 42858

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25790

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

South Asian (SAS) AF: 0.00 AC: 0 AN: 85228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53246

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109810

Other (OTH) AF: 0.00 AC: 0 AN: 60070

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.67
DEOGEN2	Benign	0.0044	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.045
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.28	N
PhyloP100		2.9
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.048
Sift	Benign	0.11	T
Sift4G	Benign	1.0	T
Polyphen		0.0030	B
Vest4		0.13
MutPred		0.41		Gain of catalytic residue at P435 (P = 0.0329)
MVP		0.54
MPC		0.017
ClinPred		0.30	T
GERP RS		5.4
Varity_R		0.12
gMVP		0.095
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs1202462843; hg19: chr11-6621444;