10-15103606-A-C

Position:

• chr10-15103606-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_183005.5(RPP38):​c.292A>C​(p.Lys98Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RPP38 NM_183005.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.08

Genes affected

RPP38 (HGNC:30329): (ribonuclease P/MRP subunit p38) Enables ribonuclease P RNA binding activity. Contributes to ribonuclease P activity. Involved in tRNA 5'-leader removal. Located in fibrillar center. Part of multimeric ribonuclease P complex. [provided by Alliance of Genome Resources, Apr 2022]

NMT2 (HGNC:7858): (N-myristoyltransferase 2) This gene encodes one of two N-myristoyltransferase proteins. N-terminal myristoylation is a lipid modification that is involved in regulating the function and localization of signaling proteins. The encoded protein catalyzes the addition of a myristoyl group to the N-terminal glycine residue of many signaling proteins, including the human immunodeficiency virus type 1 (HIV-1) proteins, Gag and Nef. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.056829244).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPP38	NM_183005.5	c.292A>C	p.Lys98Gln	missense_variant	3/3	ENST00000378197.5	NP_892117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPP38	ENST00000378197.5	c.292A>C	p.Lys98Gln	missense_variant	3/3	1	NM_183005.5	ENSP00000367439	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461822 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727204

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

May 06, 2022

The c.292A>C (p.K98Q) alteration is located in exon 3 (coding exon 1) of the RPP38 gene. This alteration results from a A to C substitution at nucleotide position 292, causing the lysine (K) at amino acid position 98 to be replaced by a glutamine (Q). 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	0.085
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.10
DANN	Benign	0.31
DEOGEN2	Benign	0.0018	T;T;T;T;T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.25	.;T;T;.;.;T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.057	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;.;N;N;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.20	N;.;N;N;N;N
REVEL	Benign	0.032
Sift	Benign	0.68	T;.;T;T;T;T
Sift4G	Benign	0.59	T;T;T;T;T;T
Polyphen		0.012	B;B;.;B;B;.
Vest4		0.18
MutPred		0.30		Loss of methylation at K98 (P = 0.0136);Loss of methylation at K98 (P = 0.0136);Loss of methylation at K98 (P = 0.0136);Loss of methylation at K98 (P = 0.0136);Loss of methylation at K98 (P = 0.0136);Loss of methylation at K98 (P = 0.0136);
MVP		0.42
MPC		0.096
ClinPred		0.030	T
GERP RS		-6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.065
gMVP		0.18

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: rs771171027; hg19: chr10-15145605;