21-43687681-T-C

Variant names:

• chr21-43687681-T-C
• rs9306160
• NM_015056.3:c.1307T>C

Variant summary

Our verdict is Benign. The variant received -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. 15/22 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 the same amino acid substitution has been previously reported as Likely benign in 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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
RRP1B	NM_015056.3	c.1307T>C	p.Leu436Pro	missense_variant	Exon 13 of 16	ENST00000340648.6	NP_055871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RRP1B	ENST00000340648.6	c.1307T>C	p.Leu436Pro	missense_variant	Exon 13 of 16	1	NM_015056.3	ENSP00000339145.4
RRP1B	ENST00000470886.1	n.970T>C		non_coding_transcript_exon_variant	Exon 2 of 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

GnomAD2 exomes AF: 0.691 AC: 167810 AN: 242928 AF XY: 0.678

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 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 AC: 31218 AN: 33132

Gnomad4 AMR exome AF: 0.827 AC: 36395 AN: 44034

Gnomad4 ASJ exome AF: 0.647 AC: 16627 AN: 25686

Gnomad4 EAS exome AF: 0.810 AC: 32019 AN: 39532

Gnomad4 SAS exome AF: 0.665 AC: 57033 AN: 85764

Gnomad4 FIN exome AF: 0.689 AC: 35848 AN: 52000

Gnomad4 NFE exome AF: 0.584 AC: 645879 AN: 1105310

Gnomad4 Remaining exome AF: 0.648 AC: 38727 AN: 59802

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 AC: 0.927578 AN: 0.927578

Gnomad4 AMR AF: 0.774 AC: 0.774052 AN: 0.774052

Gnomad4 ASJ AF: 0.649 AC: 0.649482 AN: 0.649482

Gnomad4 EAS AF: 0.817 AC: 0.817181 AN: 0.817181

Gnomad4 SAS AF: 0.683 AC: 0.683382 AN: 0.683382

Gnomad4 FIN AF: 0.695 AC: 0.695 AN: 0.695

Gnomad4 NFE AF: 0.596 AC: 0.595908 AN: 0.595908

Gnomad4 OTH AF: 0.708 AC: 0.708333 AN: 0.708333

Alfa AF: 0.633 Hom.: 41224

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
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
Mutation Taster		=99/1	polymorphism (auto)

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;