chr15-41517684-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015540.4(RPAP1):​c.4040G>A​(p.Arg1347Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,612,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

RPAP1
NM_015540.4 missense

Scores

1
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.21
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.073458105).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RPAP1NM_015540.4 linkc.4040G>A p.Arg1347Gln missense_variant Exon 25 of 25 ENST00000304330.9 NP_056355.2 Q9BWH6-1A8K2F9
RPAP1XM_005254297.2 linkc.4040G>A p.Arg1347Gln missense_variant Exon 25 of 25 XP_005254354.1 Q9BWH6-1
RPAP1XM_047432374.1 linkc.3860G>A p.Arg1287Gln missense_variant Exon 24 of 24 XP_047288330.1
RPAP1XM_047432375.1 linkc.3860G>A p.Arg1287Gln missense_variant Exon 24 of 24 XP_047288331.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RPAP1ENST00000304330.9 linkc.4040G>A p.Arg1347Gln missense_variant Exon 25 of 25 1 NM_015540.4 ENSP00000306123.4 Q9BWH6-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152094
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
250700
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135454
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0000656
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000123
AC:
18
AN:
1459974
Hom.:
0
Cov.:
32
AF XY:
0.0000110
AC XY:
8
AN XY:
725966
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000384
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000108
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152212
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74394
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000189
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Aug 27, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.4040G>A (p.R1347Q) alteration is located in exon 25 (coding exon 24) of the RPAP1 gene. This alteration results from a G to A substitution at nucleotide position 4040, causing the arginine (R) at amino acid position 1347 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
0.082
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.52
CADD
Benign
22
DANN
Benign
0.92
DEOGEN2
Benign
0.0049
T
Eigen
Benign
0.020
Eigen_PC
Benign
0.085
FATHMM_MKL
Benign
0.70
D
LIST_S2
Benign
0.41
T
M_CAP
Benign
0.018
T
MetaRNN
Benign
0.073
T
PROVEAN
Benign
0.24
N
Sift
Pathogenic
0.0
D
Vest4
0.19
MVP
0.37
ClinPred
0.37
T
GERP RS
2.3

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs138155923; hg19: chr15-41809882; COSMIC: COSV55492234; COSMIC: COSV55492234; API