1-92333446-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_024813.3(RPAP2):c.1511G>T(p.Arg504Leu) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R504C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPAP2 NM_024813.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.02

Genes affected

RPAP2 (HGNC:25791): (RNA polymerase II associated protein 2) Enables RNA polymerase II CTD heptapeptide repeat phosphatase activity. Involved in dephosphorylation of RNA polymerase II C-terminal domain and snRNA transcription. Located in cytosol and nucleolus. Part of RNA polymerase II, holoenzyme. [provided by Alliance of Genome Resources, Apr 2022]

GLMN (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.816

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPAP2	NM_024813.3	c.1511G>T	p.Arg504Leu	missense_variant	9/13	ENST00000610020.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPAP2	ENST00000610020.2	c.1511G>T	p.Arg504Leu	missense_variant	9/13	1	NM_024813.3	P1
RPAP2	ENST00000477322.1	n.205G>T		non_coding_transcript_exon_variant	1/5	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

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

Nov 22, 2022

The c.1511G>T (p.R504L) alteration is located in exon 9 (coding exon 9) of the RPAP2 gene. This alteration results from a G to T substitution at nucleotide position 1511, causing the arginine (R) at amino acid position 504 to be replaced by a leucine (L). 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	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.015	T
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Uncertain	2.8	M
PrimateAI	Benign	0.47	T
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.49		Loss of MoRF binding (P = 0.0365);
MVP		0.61
MPC		0.42
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-92799003;