9-34611107-C-T

Variant names:

• chr9-34611107-C-T
• rs1244914283
• NM_148178.3:c.190G>A

Variant summary

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

The NM_148178.3(RPP25L):​c.190G>A​(p.Ala64Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 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)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: RPP25L NM_148178.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.29

Genes affected

RPP25L (HGNC:19909): (ribonuclease P/MRP subunit p25 like) This gene encodes a protein that appears to belong to a family of evolutionarily related proteins (DUF78), that may share one or more domains in common. Members of this family are small archaebacterial proteins with no known function. Alternative splicing has been observed at this locus and two variants, both encoding the same protein, have been identified. [provided by RefSeq, Jul 2008]

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=0.06865418).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPP25L	NM_148178.3	c.190G>A	p.Ala64Thr	missense_variant	Exon 2 of 2	ENST00000378959.9	NP_680544.1
RPP25L	NM_148179.3	c.190G>A	p.Ala64Thr	missense_variant	Exon 2 of 2		NP_680545.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPP25L	ENST00000378959.9	c.190G>A	p.Ala64Thr	missense_variant	Exon 2 of 2	1	NM_148178.3	ENSP00000368242.4
RPP25L	ENST00000297613.4	c.190G>A	p.Ala64Thr	missense_variant	Exon 2 of 2	2		ENSP00000297613.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251292 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135848

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461850 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.190G>A (p.A64T) alteration is located in exon 2 (coding exon 1) of the RPP25L gene. This alteration results from a G to A substitution at nucleotide position 190, causing the alanine (A) at amino acid position 64 to be replaced by a threonine (T). 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	0.10
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.58
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.050	T;T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.75	.;T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.069	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.36	N;N
REVEL	Benign	0.075
Sift	Benign	0.40	T;T
Sift4G	Benign	0.25	T;T
Polyphen		0.0030	B;B
Vest4		0.072
MutPred		0.39		Gain of phosphorylation at A64 (P = 0.036);Gain of phosphorylation at A64 (P = 0.036);
MVP		0.043
MPC		0.39
ClinPred		0.12	T
GERP RS		2.4
Varity_R		0.051
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1244914283; hg19: chr9-34611104;