chr18-36027033-G-T

Position:

• chr18-36027033-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018170.5(RPRD1A):​c.656C>A​(p.Ala219Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPRD1A NM_018170.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.95

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]

RPRD1A (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPRD1A	NM_018170.5	c.656C>A	p.Ala219Glu	missense_variant	6/7	ENST00000399022.9	NP_060640.2
RPRD1A	NM_001303413.2	c.656C>A	p.Ala219Glu	missense_variant	6/7		NP_001290342.1
RPRD1A	NM_001303411.2	c.548C>A	p.Ala183Glu	missense_variant	7/8		NP_001290340.1
RPRD1A	NM_001303412.2	c.548C>A	p.Ala183Glu	missense_variant	7/9		NP_001290341.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPRD1A	ENST00000399022.9	c.656C>A	p.Ala219Glu	missense_variant	6/7	1	NM_018170.5	ENSP00000381984.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Nov 11, 2024

The c.656C>A (p.A219E) alteration is located in exon 6 (coding exon 6) of the RPRD1A gene. This alteration results from a C to A substitution at nucleotide position 656, causing the alanine (A) at amino acid position 219 to be replaced by a glutamic acid (E). 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	.;T;T;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;.;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Uncertain	-0.017	T
MutationAssessor	Uncertain	2.7	.;M;M;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.7	.;D;D;.
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0010	.;D;D;.
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.90
MutPred		0.57		.;Gain of disorder (P = 0.0341);Gain of disorder (P = 0.0341);.;
MVP		0.68
MPC		1.3
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.92
gMVP		0.84

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: chr18-33606996;