chr15-41517613-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_015540.4(RPAP1):​c.4111C>A​(p.Pro1371Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,610,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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

4
2
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.39
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 Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
BayesDel_addAF computational evidence supports a deleterious effect, 0.464

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RPAP1NM_015540.4 linkuse as main transcriptc.4111C>A p.Pro1371Thr missense_variant 25/25 ENST00000304330.9
RPAP1XM_005254297.2 linkuse as main transcriptc.4111C>A p.Pro1371Thr missense_variant 25/25
RPAP1XM_047432374.1 linkuse as main transcriptc.3931C>A p.Pro1311Thr missense_variant 24/24
RPAP1XM_047432375.1 linkuse as main transcriptc.3931C>A p.Pro1311Thr missense_variant 24/24

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RPAP1ENST00000304330.9 linkuse as main transcriptc.4111C>A p.Pro1371Thr missense_variant 25/251 NM_015540.4 P1Q9BWH6-1
RPAP1ENST00000565167.1 linkuse as main transcriptn.1275C>A non_coding_transcript_exon_variant 4/41
RPAP1ENST00000562303.5 linkuse as main transcriptc.*1412C>A 3_prime_UTR_variant, NMD_transcript_variant 24/241 Q9BWH6-2
RPAP1ENST00000561603.5 linkuse as main transcriptc.3354C>A p.Cys1118Ter stop_gained 24/245

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152200
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1458730
Hom.:
0
Cov.:
31
AF XY:
0.00000276
AC XY:
2
AN XY:
725404
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000904
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152200
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 21, 2022The c.4111C>A (p.P1371T) alteration is located in exon 25 (coding exon 24) of the RPAP1 gene. This alteration results from a C to A substitution at nucleotide position 4111, causing the proline (P) at amino acid position 1371 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
Uncertain
0.38
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Benign
-0.12
CADD
Uncertain
25
DANN
Uncertain
0.98
Eigen
Pathogenic
0.82
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Pathogenic
0.99
D
MutationTaster
Benign
1.0
D;D
Vest4
0.15
ClinPred
1.0
D
GERP RS
5.6

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: rs1418290690; hg19: chr15-41809811; API