Variant 12-47670324-T-G 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_024604.3(RPAP3):c.1309A>C(p.Ile437Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,446,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RPAP3
NM_024604.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.07

Variant links:

Genes affected

RPAP3 (HGNC:26151): (RNA polymerase II associated protein 3) This gene encodes an RNA polymerase II-associated protein. The encoded protein may function in transcriptional regulation and may also regulate apoptosis. Alternatively spliced transcript variants have been described. [provided by RefSeq, Mar 2009]

RPAP3 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=0.2436946).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RPAP3	NM_024604.3 linkuse as main transcript	c.1309A>C	p.Ile437Leu	missense_variant	13/17	ENST00000005386.8	NP_078880.2
RPAP3	NM_001146075.2 linkuse as main transcript	c.1207A>C	p.Ile403Leu	missense_variant	12/16		NP_001139547.1
RPAP3	NM_001146076.2 linkuse as main transcript	c.832A>C	p.Ile278Leu	missense_variant	12/16		NP_001139548.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPAP3	ENST00000005386.8 linkuse as main transcript	c.1309A>C	p.Ile437Leu	missense_variant	13/17	2	NM_024604.3	ENSP00000005386	P1	Q9H6T3-1
RPAP3	ENST00000380650.4 linkuse as main transcript	c.1207A>C	p.Ile403Leu	missense_variant	12/16	1		ENSP00000370024		Q9H6T3-2
RPAP3	ENST00000432584.7 linkuse as main transcript	c.832A>C	p.Ile278Leu	missense_variant	12/16	2		ENSP00000401823		Q9H6T3-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248916

Hom.:

AF XY:

0.00000743

AC XY:

AN XY:

134572

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000546

Gnomad SAS 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:

0.00000138

AC:

AN:

1446040

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

719964

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000506

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Feb 17, 2024

The c.1309A>C (p.I437L) alteration is located in exon 13 (coding exon 12) of the RPAP3 gene. This alteration results from a A to C substitution at nucleotide position 1309, causing the isoleucine (I) at amino acid position 437 to be replaced by a leucine (L). 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

0.30

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

T;.;.

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.74

T;T;T

M_CAP

Benign

0.0057

MetaRNN

Benign

0.24

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.6

M;.;.

MutationTaster

Benign

0.95

D;D;D

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.6

N;N;N

REVEL

Benign

0.16

Sift

Uncertain

0.011

D;D;T

Sift4G

Uncertain

0.015

D;D;T

Polyphen

0.57

P;.;P

Vest4

0.50

MutPred

0.33

Gain of ubiquitination at K434 (P = 0.0728);.;.;

MVP

0.16

MPC

0.063

ClinPred

0.60

GERP RS

5.8

Varity_R

0.30

gMVP

0.28

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

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