21-43687681-T-C

Variant names:

• chr21-43687681-T-C
• rs9306160
• NM_015056.3:c.1307T>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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

• 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 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

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
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;