21-43687681-T-C

Position:

• chr21-43687681-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015056.3(RRP1B):​c.1307T>C​(p.Leu436Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.629 in 1,603,196 control chromosomes in the GnomAD database, including 324,593 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L436V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.72 (41567 hom., cov: 34)
  • Exomes 𝑓: 0.62 (283026 hom.)
• Consequence: RRP1B NM_015056.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.116

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0867853E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.92 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RRP1B	NM_015056.3	c.1307T>C	p.Leu436Pro	missense_variant	13/16	ENST00000340648.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RRP1B	ENST00000340648.6	c.1307T>C	p.Leu436Pro	missense_variant	13/16	1	NM_015056.3	P1
RRP1B	ENST00000470886.1	n.970T>C		non_coding_transcript_exon_variant	2/5	2

Frequencies

GnomAD3 genomes AF: 0.725 AC: 110219 AN: 152122 Hom.: 41498 Cov.: 34

Gnomad AFR AF: 0.927

Gnomad AMI AF: 0.629

Gnomad AMR AF: 0.774

Gnomad ASJ AF: 0.649

Gnomad EAS AF: 0.817

Gnomad SAS AF: 0.685

Gnomad FIN AF: 0.695

Gnomad MID AF: 0.737

Gnomad NFE AF: 0.596

Gnomad OTH AF: 0.704

GnomAD3 exomes AF: 0.691 AC: 167810 AN: 242928 Hom.: 59468 AF XY: 0.678 AC XY: 89765 AN XY: 132462

Gnomad AFR exome AF: 0.935

Gnomad AMR exome AF: 0.834

Gnomad ASJ exome AF: 0.641

Gnomad EAS exome AF: 0.806

Gnomad SAS exome AF: 0.669

Gnomad FIN exome AF: 0.694

Gnomad NFE exome AF: 0.603

Gnomad OTH exome AF: 0.669

GnomAD4 exome AF: 0.619 AC: 897704 AN: 1450956 Hom.: 283026 Cov.: 60 AF XY: 0.618 AC XY: 445336 AN XY: 720396

Gnomad4 AFR exome AF: 0.942

Gnomad4 AMR exome AF: 0.827

Gnomad4 ASJ exome AF: 0.647

Gnomad4 EAS exome AF: 0.810

Gnomad4 SAS exome AF: 0.665

Gnomad4 FIN exome AF: 0.689

Gnomad4 NFE exome AF: 0.584

Gnomad4 OTH exome AF: 0.648

GnomAD4 genome AF: 0.725 AC: 110345 AN: 152240 Hom.: 41567 Cov.: 34 AF XY: 0.732 AC XY: 54471 AN XY: 74428

Gnomad4 AFR AF: 0.928

Gnomad4 AMR AF: 0.774

Gnomad4 ASJ AF: 0.649

Gnomad4 EAS AF: 0.817

Gnomad4 SAS AF: 0.683

Gnomad4 FIN AF: 0.695

Gnomad4 NFE AF: 0.596

Gnomad4 OTH AF: 0.708

Alfa AF: 0.625 Hom.: 27923

Bravo AF: 0.738

TwinsUK AF: 0.564 AC: 2093

ALSPAC AF: 0.585 AC: 2256

ESP6500AA AF: 0.925 AC: 4068

ESP6500EA AF: 0.591 AC: 5076

ExAC AF: 0.687 AC: 83163

Asia WGS AF: 0.785 AC: 2730 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.52
DANN	Benign	0.11
DEOGEN2	Benign	0.0075	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.34	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.68	N
REVEL	Benign	0.017
Sift4G	Benign	0.27	T
Polyphen		0.0	B
Vest4		0.011
MPC		0.55
ClinPred		0.00070	T
GERP RS		-3.2
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.10
gMVP		0.17

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

Other links and lift over

dbSNP: rs9306160; hg19: chr21-45107562; COSMIC: COSV61478926;