Genetic Variant NM_015540.4:c.3896G>A (chr15-41518082-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_015540.4(RPAP1):c.3896G>A(p.Arg1299His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000707 in 1,611,670 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000071 ( 2 hom. )

Consequence

RPAP1
NM_015540.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -3.64

Publications

0 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: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0387744).

BP6

Variant 15-41518082-C-T is Benign according to our data. Variant chr15-41518082-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3155931.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015540.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPAP1	NM_015540.4	MANE Select	c.3896G>A	p.Arg1299His	missense	Exon 23 of 25	NP_056355.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPAP1	ENST00000304330.9	TSL:1 MANE Select	c.3896G>A	p.Arg1299His	missense	Exon 23 of 25	ENSP00000306123.4	Q9BWH6-1
RPAP1	ENST00000562303.5	TSL:1	n.*1049G>A		non_coding_transcript_exon	Exon 23 of 24	ENSP00000455363.1	Q9BWH6-2
RPAP1	ENST00000565167.1	TSL:1	n.912G>A		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000604

AC:

AN:

248288

AF XY:

0.0000893

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000548

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000713

AC:

104

AN:

1459350

Hom.:

Cov.:

AF XY:

0.0000758

AC XY:

AN XY:

726036

show subpopulations

African (AFR)

AF:

0.0000600

AC:

AN:

33328

American (AMR)

AF:

0.00

AC:

AN:

43740

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25998

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.000314

AC:

AN:

85868

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.0000657

AC:

AN:

1111302

Other (OTH)

AF:

0.0000166

AC:

AN:

60256

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.0000657

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41584

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.0000564

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000576

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.16

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0028

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.20

M_CAP

Benign

0.00085

MetaRNN

Benign

0.039

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.26

PhyloP100

-3.6

PrimateAI

Benign

0.23

PROVEAN

Benign

0.080

REVEL

Benign

0.036

Sift

Benign

0.14

Sift4G

Benign

0.19

Polyphen

0.0

Vest4

0.17

MutPred

0.44

Loss of helix (P = 0.0558)

MVP

0.11

MPC

0.25

ClinPred

0.027

GERP RS

-5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.019

gMVP

0.11

Mutation Taster

=95/5

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over