Genetic Variant RPP40:p.Ser224Arg (chr6-4996308-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006638.4(RPP40):c.672C>A(p.Ser224Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,240 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Consequence

RPP40
NM_006638.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.582

Variant links:

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]

RPP40 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPP40	NM_006638.4 link	c.672C>A	p.Ser224Arg	missense_variant	Exon 6 of 8	ENST00000380051.7	NP_006629.2	O75818-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RPP40	ENST00000380051.7 link	c.672C>A	p.Ser224Arg	missense_variant	Exon 6 of 8	5	NM_006638.4	ENSP00000369391.2	O75818-1
RPP40	ENST00000319533.9 link	c.603C>A	p.Ser201Arg	missense_variant	Exon 5 of 7	1		ENSP00000317998.5	O75818-2
RPP40	ENST00000618533.4 link	c.546C>A	p.Ser182Arg	missense_variant	Exon 5 of 7	5		ENSP00000484334.1	A0A087X1N3
RPP40	ENST00000464646.1 link	c.492C>A	p.Ser164Arg	missense_variant	Exon 6 of 8	5		ENSP00000419431.1	X6RLL4

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000604

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.672C>A (p.S224R) alteration is located in exon 6 (coding exon 6) of the RPP40 gene. This alteration results from a C to A substitution at nucleotide position 672, causing the serine (S) at amino acid position 224 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.012

T;.;T;T

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.25

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Benign

0.033

MetaRNN

Uncertain

0.59

D;D;D;D

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.7

M;.;.;.

PrimateAI

Benign

0.45

PROVEAN

Benign

-2.0

N;N;.;N

REVEL

Uncertain

0.34

Sift

Uncertain

0.016

D;D;.;D

Sift4G

Benign

0.071

T;T;T;T

Polyphen

0.97

D;D;.;.

Vest4

0.64

MutPred

0.49

Loss of disorder (P = 0.0764);.;.;.;

MVP

0.51

MPC

0.79

ClinPred

0.93

GERP RS

2.0

Varity_R

0.45

gMVP

0.57

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over