Variant 15-41517666-T-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_015540.4(RPAP1):c.4058A>G(p.Tyr1353Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

RPAP1
NM_015540.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.05

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]

RPAP1 links:

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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=0.22665522).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
RPAP1	NM_015540.4 linkuse as main transcript	c.4058A>G	p.Tyr1353Cys	missense_variant	25/25	ENST00000304330.9
RPAP1	XM_005254297.2 linkuse as main transcript	c.4058A>G	p.Tyr1353Cys	missense_variant	25/25
RPAP1	XM_047432374.1 linkuse as main transcript	c.3878A>G	p.Tyr1293Cys	missense_variant	24/24
RPAP1	XM_047432375.1 linkuse as main transcript	c.3878A>G	p.Tyr1293Cys	missense_variant	24/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPAP1	ENST00000304330.9 linkuse as main transcript	c.4058A>G	p.Tyr1353Cys	missense_variant	25/25	1	NM_015540.4	P1	Q9BWH6-1
RPAP1	ENST00000565167.1 linkuse as main transcript	n.1222A>G		non_coding_transcript_exon_variant	4/4	1
RPAP1	ENST00000562303.5 linkuse as main transcript	c.*1359A>G		3_prime_UTR_variant, NMD_transcript_variant	24/24	1			Q9BWH6-2
RPAP1	ENST00000561603.5 linkuse as main transcript	c.3301A>G	p.Ile1101Val	missense_variant	24/24	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250584

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135412

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:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1460590

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726446

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:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

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

Aug 04, 2023

The c.4058A>G (p.Y1353C) alteration is located in exon 25 (coding exon 24) of the RPAP1 gene. This alteration results from a A to G substitution at nucleotide position 4058, causing the tyrosine (Y) at amino acid position 1353 to be replaced by a cysteine (C). 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

0.32

BayesDel_addAF

Benign

-0.048

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

DANN

Benign

0.96

DEOGEN2

Benign

0.0083

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.30

M_CAP

Benign

0.047

MetaRNN

Benign

0.23

MutationTaster

Benign

1.0

D;N

PROVEAN

Benign

-0.22

Sift

Pathogenic

0.0

Vest4

0.19

MVP

0.42

ClinPred

0.99

GERP RS

5.6

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over