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. 15/21 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 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
• Publications: 44 publications found

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015056.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RRP1B	NM_015056.3	MANE Select	c.1307T>C	p.Leu436Pro	missense	Exon 13 of 16	NP_055871.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RRP1B	ENST00000340648.6	TSL:1 MANE Select	c.1307T>C	p.Leu436Pro	missense	Exon 13 of 16	ENSP00000339145.4
	RRP1B	ENST00000470886.1	TSL:2	n.970T>C		non_coding_transcript_exon	Exon 2 of 5

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

African (AFR) AF: 0.942 AC: 31218 AN: 33132

American (AMR) AF: 0.827 AC: 36395 AN: 44034

Ashkenazi Jewish (ASJ) AF: 0.647 AC: 16627 AN: 25686

East Asian (EAS) AF: 0.810 AC: 32019 AN: 39532

South Asian (SAS) AF: 0.665 AC: 57033 AN: 85764

European-Finnish (FIN) AF: 0.689 AC: 35848 AN: 52000

Middle Eastern (MID) AF: 0.695 AC: 3958 AN: 5696

European-Non Finnish (NFE) AF: 0.584 AC: 645879 AN: 1105310

Other (OTH) 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

African (AFR) AF: 0.928 AC: 38552 AN: 41562

American (AMR) AF: 0.774 AC: 11843 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.649 AC: 2255 AN: 3472

East Asian (EAS) AF: 0.817 AC: 4233 AN: 5180

South Asian (SAS) AF: 0.683 AC: 3298 AN: 4826

European-Finnish (FIN) AF: 0.695 AC: 7367 AN: 10600

Middle Eastern (MID) AF: 0.735 AC: 216 AN: 294

European-Non Finnish (NFE) AF: 0.596 AC: 40511 AN: 67982

Other (OTH) AF: 0.708 AC: 1496 AN: 2112

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 v4.9

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
PhyloP100		-0.12
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

Other links and lift over

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