chr18-36033709-T-C

Position:

• chr18-36033709-T-C

Variant summary

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

The NM_018170.5(RPRD1A):​c.280A>G​(p.Ser94Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPRD1A NM_018170.5 missense, splice_region
• Scores: Splicing: ADA: 0.9775
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

Genes affected

RPRD1A (HGNC:25560): (regulation of nuclear pre-mRNA domain containing 1A) This gene encodes a cell-cycle and transcription regulatory protein. The encoded protein interacts with the cell cycle inhibitor cyclin-dependent kinase 4 inhibitor B and may function as a negative regulator of G(1)/S phase progression. This protein also forms homo- and hetrodimers with the protein, regulation of nuclear pre-mRNA domain-containing protein 1B, to form a scaffold that interacts with the C-terminal domain of RNA polymerase II subunit B1 and regulates several aspects of transcription. Alternate splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 16. [provided by RefSeq, Dec 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPRD1A	NM_018170.5	c.280A>G	p.Ser94Gly	missense_variant, splice_region_variant	2/7	ENST00000399022.9	NP_060640.2
RPRD1A	NM_001303413.2	c.280A>G	p.Ser94Gly	missense_variant, splice_region_variant	2/7		NP_001290342.1
RPRD1A	NM_001303411.2	c.172A>G	p.Ser58Gly	missense_variant, splice_region_variant	3/8		NP_001290340.1
RPRD1A	NM_001303412.2	c.172A>G	p.Ser58Gly	missense_variant, splice_region_variant	3/9		NP_001290341.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPRD1A	ENST00000399022.9	c.280A>G	p.Ser94Gly	missense_variant, splice_region_variant	2/7	1	NM_018170.5	ENSP00000381984.3

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

Oct 13, 2023

The c.280A>G (p.S94G) alteration is located in exon 2 (coding exon 2) of the RPRD1A gene. This alteration results from a A to G substitution at nucleotide position 280, causing the serine (S) at amino acid position 94 to be replaced by a glycine (G). 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	0.063
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.037	.;T;T;.
Eigen	Benign	-0.13
Eigen_PC	Benign	0.10
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	.;.;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.12	.;N;N;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.70	.;N;N;.
REVEL	Benign	0.082
Sift	Benign	0.51	.;T;T;.
Sift4G	Benign	0.41	T;T;T;T
Polyphen		0.0020	B;B;B;B
Vest4		0.24
MutPred		0.35		.;Loss of phosphorylation at S94 (P = 0.0442);Loss of phosphorylation at S94 (P = 0.0442);.;
MVP		0.25
MPC		1.4
ClinPred		0.89	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.77
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: -26

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: chr18-33613672;