15-41520849-C-T

Variant names:

• chr15-41520849-C-T
• rs774890309
• NM_015540.4:c.3337G>A

Variant summary

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

The NM_015540.4(RPAP1):​c.3337G>A​(p.Ala1113Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00007 in 1,613,716 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000068 (1 hom.)
• Consequence: RPAP1 NM_015540.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.18

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

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.06408119).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPAP1	NM_015540.4	c.3337G>A	p.Ala1113Thr	missense_variant	Exon 22 of 25	ENST00000304330.9	NP_056355.2
RPAP1	XM_005254297.2	c.3337G>A	p.Ala1113Thr	missense_variant	Exon 22 of 25		XP_005254354.1
RPAP1	XM_047432374.1	c.3157G>A	p.Ala1053Thr	missense_variant	Exon 21 of 24		XP_047288330.1
RPAP1	XM_047432375.1	c.3157G>A	p.Ala1053Thr	missense_variant	Exon 21 of 24		XP_047288331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPAP1	ENST00000304330.9	c.3337G>A	p.Ala1113Thr	missense_variant	Exon 22 of 25	1	NM_015540.4	ENSP00000306123.4
RPAP1	ENST00000562303.5	n.3337G>A		non_coding_transcript_exon_variant	Exon 22 of 24	1		ENSP00000455363.1
RPAP1	ENST00000565167.1	n.353G>A		non_coding_transcript_exon_variant	Exon 2 of 4	1
RPAP1	ENST00000561603.5	c.3038+889G>A		intron_variant	Intron 21 of 23	5		ENSP00000456207.1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.0000882

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000152 AC: 38 AN: 250632 AF XY: 0.0000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.0000677 AC: 99 AN: 1461556 Hom.: 1 Cov.: 30 AF XY: 0.0000481 AC XY: 35 AN XY: 727078

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.000738 AC: 33 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53096

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000486 AC: 54 AN: 1112004

Other (OTH) AF: 0.000182 AC: 11 AN: 60394

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74328

African (AFR) AF: 0.00 AC: 0 AN: 41448

American (AMR) AF: 0.000327 AC: 5 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68030

Other (OTH) AF: 0.00143 AC: 3 AN: 2094

Alfa AF: 0.0000643 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 23, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3337G>A (p.A1113T) alteration is located in exon 22 (coding exon 21) of the RPAP1 gene. This alteration results from a G to A substitution at nucleotide position 3337, causing the alanine (A) at amino acid position 1113 to be replaced by a threonine (T). 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	0.089
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0035	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.2
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.13
Sift	Uncertain	0.028	D
Sift4G	Benign	0.20	T
Polyphen		0.27	B
Vest4		0.25
MutPred		0.50		Gain of relative solvent accessibility (P = 0.0479);
MVP		0.76
MPC		0.38
ClinPred		0.060	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.057
gMVP		0.15
Mutation Taster		=97/3	polymorphism

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: rs774890309; hg19: chr15-41813047;