chr15-41517613-G-T
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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
NM_015540.4 missense
Scores
4
2
2
Clinical Significance
Conservation
PhyloP100: 7.39
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]
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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 |
---|---|---|---|---|---|---|---|
RPAP1 | NM_015540.4 | c.4111C>A | p.Pro1371Thr | missense_variant | 25/25 | ENST00000304330.9 | |
RPAP1 | XM_005254297.2 | c.4111C>A | p.Pro1371Thr | missense_variant | 25/25 | ||
RPAP1 | XM_047432374.1 | c.3931C>A | p.Pro1311Thr | missense_variant | 24/24 | ||
RPAP1 | XM_047432375.1 | c.3931C>A | p.Pro1311Thr | missense_variant | 24/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RPAP1 | ENST00000304330.9 | c.4111C>A | p.Pro1371Thr | missense_variant | 25/25 | 1 | NM_015540.4 | P1 | |
RPAP1 | ENST00000565167.1 | n.1275C>A | non_coding_transcript_exon_variant | 4/4 | 1 | ||||
RPAP1 | ENST00000562303.5 | c.*1412C>A | 3_prime_UTR_variant, NMD_transcript_variant | 24/24 | 1 | ||||
RPAP1 | ENST00000561603.5 | c.3354C>A | p.Cys1118Ter | stop_gained | 24/24 | 5 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152200Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1458730Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2AN XY: 725404
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152200Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74362
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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 submitter | clinical testing | Ambry Genetics | Nov 21, 2022 | The 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
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Name
Calibrated prediction
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Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D
Vest4
ClinPred
D
GERP RS
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at