dbSNP rs760975387: RPP21:p.Thr129Pro (chr6-30346723-A-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001199121.3(RPP21):c.385A>C(p.Thr129Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T129S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

RPP21
NM_001199121.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.305

Publications

0 publications found

Variant links:

Genes affected

RPP21 (HGNC:21300): (ribonuclease P/MRP subunit p21) RPP21 is a protein subunit of nuclear ribonuclease P, which processes the 5-prime leader sequence of precursor tRNAs (Jarrous et al., 2001 [PubMed 11497433]).[supplied by OMIM, Jan 2009]

RPP21 links:

TRIM39-RPP21 (HGNC:38845): (TRIM39-RPP21 readthrough) This locus represents naturally occurring read-through transcription between the neighboring TRIM39 (tripartite motif-containing 39) and RPP21 (ribonuclease P/MRP 21kDa subunit) genes on chromosome 6. The read-through transcript encodes a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Nov 2010]

TRIM39-RPP21 links:

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ACMG classification

Classification was made for transcript

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 (MetaRNN=0.05139932).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001199121.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPP21	NM_024839.4	MANE Select	c.378A>C	p.Pro126Pro	synonymous	Exon 5 of 5	NP_079115.1	Q9H633-1
RPP21	NM_001199121.3		c.385A>C	p.Thr129Pro	missense	Exon 5 of 5	NP_001186050.1	Q9H633-3
TRIM39-RPP21	NM_001199119.1		c.1425A>C	p.Pro475Pro	synonymous	Exon 10 of 10	NP_001186048.1	A0A096LP39

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPP21	ENST00000436442.2	TSL:1	c.385A>C	p.Thr129Pro	missense	Exon 5 of 5	ENSP00000397778.2	Q9H633-3
RPP21	ENST00000442966.7	TSL:1 MANE Select	c.378A>C	p.Pro126Pro	synonymous	Exon 5 of 5	ENSP00000403833.2	Q9H633-1
TRIM39-RPP21	ENST00000623385.3	TSL:5	c.1425A>C	p.Pro475Pro	synonymous	Exon 11 of 11	ENSP00000485378.1	A0A096LP39

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000283

AC:

AN:

247080

AF XY:

0.0000372

show subpopulations

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:

0.0000631

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461234

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726920

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52768

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000144

AC:

AN:

1112010

Other (OTH)

AF:

0.0000331

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000582

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.46

CADD

Benign

6.7

(source)

DANN

Benign

0.75

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.043

M_CAP

Benign

0.0022

MetaRNN

Benign

0.051

MetaSVM

Benign

-1.0

PhyloP100

0.30

PROVEAN

Benign

0.99

REVEL

Benign

0.017

Sift

Benign

0.28

Sift4G

Benign

0.26

Polyphen

0.0

Vest4

0.22

MutPred

0.24

Gain of loop (P = 0.0045)

MVP

0.17

ClinPred

0.045

GERP RS

-5.5

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over