Genetic Variant RPAP1:p.Arg1035Ser (chr15-41521081-C-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_015540.4(RPAP1):c.3105G>T(p.Arg1035Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000333 in 1,530,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

RPAP1
NM_015540.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.621

Publications

20 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01407367).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPAP1	NM_015540.4 link	c.3105G>T	p.Arg1035Ser	missense_variant	Exon 22 of 25	ENST00000304330.9	NP_056355.2	Q9BWH6-1A8K2F9
RPAP1	XM_005254297.2 link	c.3105G>T	p.Arg1035Ser	missense_variant	Exon 22 of 25		XP_005254354.1	Q9BWH6-1
RPAP1	XM_047432374.1 link	c.2925G>T	p.Arg975Ser	missense_variant	Exon 21 of 24		XP_047288330.1
RPAP1	XM_047432375.1 link	c.2925G>T	p.Arg975Ser	missense_variant	Exon 21 of 24		XP_047288331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RPAP1	ENST00000304330.9 link	c.3105G>T	p.Arg1035Ser	missense_variant	Exon 22 of 25	1	NM_015540.4	ENSP00000306123.4	Q9BWH6-1
RPAP1	ENST00000562303.5 link	n.3105G>T		non_coding_transcript_exon_variant	Exon 22 of 24	1		ENSP00000455363.1	Q9BWH6-2
RPAP1	ENST00000565167.1 link	n.121G>T		non_coding_transcript_exon_variant	Exon 2 of 4	1
RPAP1	ENST00000561603.5 link	c.3038+657G>T		intron_variant	Intron 21 of 23	5		ENSP00000456207.1	H3BRE8

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

151974

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000852

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

GnomAD2 exomes

AF:

0.000151

AC:

AN:

185632

AF XY:

0.000102

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00121

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000276

AC:

AN:

1378786

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

676926

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30924

American (AMR)

AF:

0.00116

AC:

AN:

31924

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20594

East Asian (EAS)

AF:

0.00

AC:

AN:

38990

South Asian (SAS)

AF:

0.0000138

AC:

AN:

72298

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49648

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5352

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1072316

Other (OTH)

AF:

0.00

AC:

AN:

56740

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000855

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41516

American (AMR)

AF:

0.000851

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67968

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

29766

ExAC

AF:

0.000108

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.52

CADD

Benign

3.9

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.00060

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.69

M_CAP

Benign

0.027

MetaRNN

Benign

0.014

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.29

PhyloP100

0.62

PrimateAI

Benign

0.23

PROVEAN

Benign

0.47

REVEL

Benign

0.14

Sift

Benign

0.68

Sift4G

Benign

0.73

Polyphen

0.0020

Vest4

0.095

MutPred

0.25

Loss of solvent accessibility (P = 0.0238);

MVP

0.65

MPC

0.24

ClinPred

0.011

GERP RS

3.9

Varity_R

0.11

gMVP

0.15

Mutation Taster

=94/6

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over