15-41520863-C-A

Position:

• chr15-41520863-C-A

Variant summary

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

The NM_015540.4(RPAP1):​c.3323G>T​(p.Arg1108Leu) 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 1,461,558 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1108G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RPAP1 NM_015540.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.14

Genes affected

RPAP1 (HGNC:24567): (RNA polymerase II associated protein 1) This protein forms part of the RNA polymerase II (RNAPII) enzyme complex and may recruit RNAPII to chromatin through its interaction with acetylated histones. [provided by RefSeq, Jul 2012]

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=0.16480353).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPAP1	NM_015540.4	c.3323G>T	p.Arg1108Leu	missense_variant	22/25	ENST00000304330.9
RPAP1	XM_005254297.2	c.3323G>T	p.Arg1108Leu	missense_variant	22/25
RPAP1	XM_047432374.1	c.3143G>T	p.Arg1048Leu	missense_variant	21/24
RPAP1	XM_047432375.1	c.3143G>T	p.Arg1048Leu	missense_variant	21/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPAP1	ENST00000304330.9	c.3323G>T	p.Arg1108Leu	missense_variant	22/25	1	NM_015540.4	P1
RPAP1	ENST00000565167.1	n.339G>T		non_coding_transcript_exon_variant	2/4	1
RPAP1	ENST00000562303.5	c.3323G>T	p.Arg1108Leu	missense_variant, NMD_transcript_variant	22/24	1
RPAP1	ENST00000561603.5	c.3038+875G>T		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461558 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727082

Gnomad4 AFR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

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

Jan 27, 2022

The c.3323G>T (p.R1108L) alteration is located in exon 22 (coding exon 21) of the RPAP1 gene. This alteration results from a G to T substitution at nucleotide position 3323, causing the arginine (R) at amino acid position 1108 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	Benign	0.10
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	14
DANN	Benign	0.82
DEOGEN2	Benign	0.0028	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.13
Sift	Benign	0.030	D
Sift4G	Benign	0.49	T
Polyphen		0.0010	B
Vest4		0.18
MutPred		0.36		Loss of disorder (P = 0.0877);
MVP		0.66
MPC		0.26
ClinPred		0.10	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.065
gMVP		0.26

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: rs377151806; hg19: chr15-41813061;