6-4995991-T-C

Position:

• chr6-4995991-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006638.4(RPP40):​c.853A>G​(p.Ile285Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RPP40 NM_006638.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.489

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18719578).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPP40	NM_006638.4	c.853A>G	p.Ile285Val	missense_variant	7/8	ENST00000380051.7	NP_006629.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPP40	ENST00000380051.7	c.853A>G	p.Ile285Val	missense_variant	7/8	5	NM_006638.4	ENSP00000369391.2
RPP40	ENST00000319533.9	c.784A>G	p.Ile262Val	missense_variant	6/7	1		ENSP00000317998.5
RPP40	ENST00000618533.4	c.727A>G	p.Ile243Val	missense_variant	6/7	5		ENSP00000484334.1
RPP40	ENST00000464646.1	c.673A>G	p.Ile225Val	missense_variant	7/8	5		ENSP00000419431.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251438 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135898

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 19, 2024

The c.853A>G (p.I285V) alteration is located in exon 7 (coding exon 7) of the RPP40 gene. This alteration results from a A to G substitution at nucleotide position 853, causing the isoleucine (I) at amino acid position 285 to be replaced by a valine (V). 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	Benign	0.11
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Benign	0.87
DEOGEN2	Benign	0.0099	T;.;T;T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.80	T;T;T;T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.;.;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.75	N;N;.;N
REVEL	Benign	0.051
Sift	Benign	0.16	T;T;.;T
Sift4G	Benign	0.27	T;T;T;T
Polyphen		0.018	B;B;.;.
Vest4		0.14
MutPred		0.60		Loss of catalytic residue at P287 (P = 0.0284);.;.;.;
MVP		0.30
MPC		0.20
ClinPred		0.083	T
GERP RS		-2.7
Varity_R		0.060
gMVP		0.40

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

Other links and lift over

dbSNP: rs781256718; hg19: chr6-4996225;