21-43685777-G-T

Position:

• chr21-43685777-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000340648.6(RRP1B):​c.997G>T​(p.Asp333Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D333N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RRP1B ENST00000340648.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.79

Genes affected

RRP1B (HGNC:23818): (ribosomal RNA processing 1B) Enables transcription coactivator activity. Involved in several processes, including cellular response to virus; positive regulation by host of viral transcription; and positive regulation of transcription by RNA polymerase II. Located in chromosome; granular component; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29762042).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RRP1B	NM_015056.3	c.997G>T	p.Asp333Tyr	missense_variant	11/16	ENST00000340648.6	NP_055871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RRP1B	ENST00000340648.6	c.997G>T	p.Asp333Tyr	missense_variant	11/16	1	NM_015056.3	ENSP00000339145.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

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

Dec 01, 2022

The c.997G>T (p.D333Y) alteration is located in exon 11 (coding exon 11) of the RRP1B gene. This alteration results from a G to T substitution at nucleotide position 997, causing the aspartic acid (D) at amino acid position 333 to be replaced by a tyrosine (Y). 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	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.097
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Benign	0.11
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.34
MutPred		0.30		Loss of disorder (P = 0.0362);
MVP		0.54
MPC		1.2
ClinPred		0.97	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.81
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: chr21-45105658; COSMIC: COSV100513278; COSMIC: COSV100513278;