rs199999883

Variant names:

• chr6-4996315-A-C
• rs199999883
• NM_006638.4:c.665T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_006638.4(RPP40):​c.665T>G​(p.Leu222Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000342 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: RPP40 NM_006638.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.57
• Publications: 0 publications found

Genes affected

RPP40 (HGNC:20992): (ribonuclease P/MRP subunit p40) Enables ribonuclease P RNA binding activity. Contributes to ribonuclease P activity. Involved in tRNA 5'-leader removal. Part of multimeric ribonuclease P complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006638.4. 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
	RPP40	NM_006638.4	MANE Select	c.665T>G	p.Leu222Arg	missense	Exon 6 of 8	NP_006629.2	O75818-1
	RPP40	NM_001286132.2		c.596T>G	p.Leu199Arg	missense	Exon 5 of 7	NP_001273061.1	O75818-2
	RPP40	NM_001286133.2		c.539T>G	p.Leu180Arg	missense	Exon 5 of 7	NP_001273062.1	A0A087X1N3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPP40	ENST00000380051.7	TSL:5 MANE Select	c.665T>G	p.Leu222Arg	missense	Exon 6 of 8	ENSP00000369391.2	O75818-1
	RPP40	ENST00000319533.9	TSL:1	c.596T>G	p.Leu199Arg	missense	Exon 5 of 7	ENSP00000317998.5	O75818-2
	RPP40	ENST00000618533.4	TSL:5	c.539T>G	p.Leu180Arg	missense	Exon 5 of 7	ENSP00000484334.1	A0A087X1N3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251434 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000342 AC: 50 AN: 1461848 Hom.: 0 Cov.: 31 AF XY: 0.0000399 AC XY: 29 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.0000441 AC: 49 AN: 1112008

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

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	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.066	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		6.6
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.93		Gain of disorder (P = 0.0198)
MVP		0.88
MPC		0.95
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.81
gMVP		0.79
Mutation Taster		=19/81	disease causing

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: rs199999883; hg19: chr6-4996549;