15-74956388-C-T

Variant names:

• chr15-74956388-C-T
• rs1212785431
• NM_017793.3:c.196G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017793.3(RPP25):​c.196G>A​(p.Val66Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,451,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RPP25 NM_017793.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.64
• Publications: 0 publications found

Genes affected

RPP25 (HGNC:30361): (ribonuclease P and MRP subunit p25) Enables ribonuclease P RNA binding activity. Contributes to ribonuclease P activity. Involved in tRNA 5'-leader removal. Located in centriolar satellite and nucleoplasm. Part of multimeric ribonuclease P complex and ribonuclease MRP complex. Biomarker of autistic disorder. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2893263).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017793.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPP25	NM_017793.3	MANE Select	c.196G>A	p.Val66Ile	missense	Exon 1 of 1	NP_060263.2	Q9BUL9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPP25	ENST00000322177.6	TSL:6 MANE Select	c.196G>A	p.Val66Ile	missense	Exon 1 of 1	ENSP00000317691.6	Q9BUL9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1451828 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2 AN XY: 722356

African (AFR) AF: 0.00 AC: 0 AN: 33330

American (AMR) AF: 0.00 AC: 0 AN: 44318

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25900

East Asian (EAS) AF: 0.00 AC: 0 AN: 39476

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85666

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46918

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110428

Other (OTH) AF: 0.00 AC: 0 AN: 60032

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	0.0011	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.067	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	2.0	M
PhyloP100		3.6
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.15
Sift	Benign	0.11	T
Sift4G	Benign	0.098	T
Polyphen		0.97	D
Vest4		0.16
MutPred		0.70		Loss of catalytic residue at V66 (P = 0.0386)
MVP		0.29
MPC		1.5
ClinPred		0.95	D
GERP RS		4.2
PromoterAI		0.082	Neutral
Varity_R		0.20
gMVP		0.53

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

Other links and lift over

dbSNP: rs1212785431; hg19: chr15-75248729;