chr6-5002104-T-C

Variant names:

• chr6-5002104-T-C
• rs1262408151
• NM_006638.4:c.265A>G

Variant summary

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

The NM_006638.4(RPP40):​c.265A>G​(p.Lys89Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,458,792 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RPP40 NM_006638.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.73

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 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	c.265A>G	p.Lys89Glu	missense_variant	Exon 2 of 8	ENST00000380051.7	NP_006629.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPP40	ENST00000380051.7	c.265A>G	p.Lys89Glu	missense_variant	Exon 2 of 8	5	NM_006638.4	ENSP00000369391.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248118 Hom.: 0 AF XY: 0.00000746 AC XY: 1 AN XY: 134014

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000548

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458792 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2 AN XY: 725714

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.265A>G (p.K89E) alteration is located in exon 2 (coding exon 2) of the RPP40 gene. This alteration results from a A to G substitution at nucleotide position 265, causing the lysine (K) at amino acid position 89 to be replaced by a glutamic acid (E). 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	0.093
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.044	T;.;T;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;T;D;D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.63	D;D;D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.8	M;M;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.5	N;D;.;D
REVEL	Benign	0.23
Sift	Uncertain	0.011	D;D;.;D
Sift4G	Uncertain	0.042	D;D;D;D
Polyphen		0.94	P;D;.;.
Vest4		0.59
MutPred		0.53		Loss of methylation at K89 (P = 0.0113);Loss of methylation at K89 (P = 0.0113);Loss of methylation at K89 (P = 0.0113);.;
MVP		0.53
MPC		0.79
ClinPred		0.85	D
GERP RS		5.3
Varity_R		0.41
gMVP		0.42

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: rs1262408151; hg19: chr6-5002338;