12-47668944-G-C

Position:

• chr12-47668944-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024604.3(RPAP3):​c.1685C>G​(p.Ser562Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 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)
• Consequence: RPAP3 NM_024604.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.79

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]

ACMG classification

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=0.11853114).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPAP3	NM_024604.3	c.1685C>G	p.Ser562Cys	missense_variant	14/17	ENST00000005386.8	NP_078880.2
RPAP3	NM_001146075.2	c.1583C>G	p.Ser528Cys	missense_variant	13/16		NP_001139547.1
RPAP3	NM_001146076.2	c.1208C>G	p.Ser403Cys	missense_variant	13/16		NP_001139548.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPAP3	ENST00000005386.8	c.1685C>G	p.Ser562Cys	missense_variant	14/17	2	NM_024604.3	ENSP00000005386.3
RPAP3	ENST00000380650.4	c.1583C>G	p.Ser528Cys	missense_variant	13/16	1		ENSP00000370024.4
RPAP3	ENST00000432584.7	c.1208C>G	p.Ser403Cys	missense_variant	13/16	2		ENSP00000401823.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 22, 2023

The c.1685C>G (p.S562C) alteration is located in exon 14 (coding exon 13) of the RPAP3 gene. This alteration results from a C to G substitution at nucleotide position 1685, causing the serine (S) at amino acid position 562 to be replaced by a cysteine (C). 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	0.072
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Benign	0.89
DEOGEN2	Benign	0.066	T;.;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.048
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.66	T;T;T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.80	N;.;.
MutationTaster	Benign	0.97	N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.2	N;N;N
REVEL	Benign	0.039
Sift	Benign	0.17	T;T;T
Sift4G	Benign	0.12	T;T;T
Polyphen		0.015	B;.;B
Vest4		0.21
MutPred		0.37		Loss of loop (P = 0.0073);.;.;
MVP		0.43
MPC		0.38
ClinPred		0.46	T
GERP RS		4.0
Varity_R		0.082
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-48062727;