15-41520864-G-C

Position:

• chr15-41520864-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_015540.4(RPAP1):​c.3322C>G​(p.Arg1108Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00046 in 1,613,874 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1108L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: RPAP1 NM_015540.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.13

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.01072821).
• BP6: Variant 15-41520864-G-C is Benign according to our data. Variant chr15-41520864-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 768696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPAP1	NM_015540.4	c.3322C>G	p.Arg1108Gly	missense_variant	22/25	ENST00000304330.9
RPAP1	XM_005254297.2	c.3322C>G	p.Arg1108Gly	missense_variant	22/25
RPAP1	XM_047432374.1	c.3142C>G	p.Arg1048Gly	missense_variant	21/24
RPAP1	XM_047432375.1	c.3142C>G	p.Arg1048Gly	missense_variant	21/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPAP1	ENST00000304330.9	c.3322C>G	p.Arg1108Gly	missense_variant	22/25	1	NM_015540.4	P1
RPAP1	ENST00000565167.1	n.338C>G		non_coding_transcript_exon_variant	2/4	1
RPAP1	ENST00000562303.5	c.3322C>G	p.Arg1108Gly	missense_variant, NMD_transcript_variant	22/24	1
RPAP1	ENST00000561603.5	c.3038+874C>G		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00230 AC: 350 AN: 152208 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00774

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

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: 0.000132

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.000595 AC: 149 AN: 250548 Hom.: 0 AF XY: 0.000575 AC XY: 78 AN XY: 135560

Gnomad AFR exome AF: 0.00694

Gnomad AMR exome AF: 0.000549

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: 0.000141

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000269 AC: 393 AN: 1461548 Hom.: 0 Cov.: 30 AF XY: 0.000272 AC XY: 198 AN XY: 727072

Gnomad4 AFR exome AF: 0.00690

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000908

Gnomad4 OTH exome AF: 0.000596

GnomAD4 genome AF: 0.00230 AC: 350 AN: 152326 Hom.: 1 Cov.: 32 AF XY: 0.00227 AC XY: 169 AN XY: 74484

Gnomad4 AFR AF: 0.00772

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.000179 Hom.: 0

Bravo AF: 0.00254

ESP6500AA AF: 0.00613 AC: 27

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000750 AC: 91

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 21, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.0050	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.036
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.14
Sift	Benign	0.33	T
Sift4G	Benign	0.41	T
Polyphen		0.011	B
Vest4		0.11
MVP		0.84
MPC		0.27
ClinPred		0.011	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.093
gMVP		0.15

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

Other links and lift over

dbSNP: rs7170898; hg19: chr15-41813062;