15-41520473-C-T

Variant summary

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

The NM_015540.4(RPAP1):​c.3713G>A​(p.Arg1238His) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,613,994 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

RPAP1
NM_015540.4 missense

Scores

3
7
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.96
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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RPAP1NM_015540.4 linkc.3713G>A p.Arg1238His missense_variant Exon 22 of 25 ENST00000304330.9 NP_056355.2 Q9BWH6-1A8K2F9
RPAP1XM_005254297.2 linkc.3713G>A p.Arg1238His missense_variant Exon 22 of 25 XP_005254354.1 Q9BWH6-1
RPAP1XM_047432374.1 linkc.3533G>A p.Arg1178His missense_variant Exon 21 of 24 XP_047288330.1
RPAP1XM_047432375.1 linkc.3533G>A p.Arg1178His missense_variant Exon 21 of 24 XP_047288331.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RPAP1ENST00000304330.9 linkc.3713G>A p.Arg1238His missense_variant Exon 22 of 25 1 NM_015540.4 ENSP00000306123.4 Q9BWH6-1
RPAP1ENST00000562303.5 linkn.3713G>A non_coding_transcript_exon_variant Exon 22 of 24 1 ENSP00000455363.1 Q9BWH6-2
RPAP1ENST00000565167.1 linkn.729G>A non_coding_transcript_exon_variant Exon 2 of 4 1
RPAP1ENST00000561603.5 linkc.3038+1265G>A intron_variant Intron 21 of 23 5 ENSP00000456207.1 H3BRE8

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152202
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000798
AC:
2
AN:
250476
Hom.:
0
AF XY:
0.00000738
AC XY:
1
AN XY:
135592
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461792
Hom.:
0
Cov.:
30
AF XY:
0.00000413
AC XY:
3
AN XY:
727192
show subpopulations
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:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152202
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000693
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 24, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.3713G>A (p.R1238H) alteration is located in exon 22 (coding exon 21) of the RPAP1 gene. This alteration results from a G to A substitution at nucleotide position 3713, causing the arginine (R) at amino acid position 1238 to be replaced by a histidine (H). 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
0.22
BayesDel_addAF
Benign
-0.015
T
BayesDel_noAF
Benign
-0.20
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.017
T
Eigen
Pathogenic
0.73
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.94
D
M_CAP
Benign
0.037
D
MetaRNN
Uncertain
0.55
D
MetaSVM
Benign
-1.2
T
MutationAssessor
Uncertain
2.4
M
PrimateAI
Uncertain
0.63
T
PROVEAN
Benign
-2.1
N
REVEL
Benign
0.21
Sift
Uncertain
0.0060
D
Sift4G
Uncertain
0.0050
D
Polyphen
1.0
D
Vest4
0.66
MutPred
0.44
Loss of MoRF binding (P = 0.0783);
MVP
0.34
MPC
0.86
ClinPred
0.99
D
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.22
gMVP
0.60

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

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

Other links and lift over

dbSNP: rs546475483; hg19: chr15-41812671; API