13-48381380-A-T

Variant names:

• chr13-48381380-A-T
• rs143948310
• NM_000321.3:c.1632A>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000321.3(RB1):​c.1632A>T​(p.Arg544Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,442 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.75

Genes affected

RB1 (HGNC:9884): (RB transcriptional corepressor 1) The protein encoded by this gene is a negative regulator of the cell cycle and was the first tumor suppressor gene found. The encoded protein also stabilizes constitutive heterochromatin to maintain the overall chromatin structure. The active, hypophosphorylated form of the protein binds transcription factor E2F1. Defects in this gene are a cause of childhood cancer retinoblastoma (RB), bladder cancer, and osteogenic sarcoma. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a region_of_interest Domain A (size 206) in uniprot entity RB_HUMAN there are 18 pathogenic changes around while only 0 benign (100%) in NM_000321.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.1632A>T	p.Arg544Ser	missense_variant	Exon 17 of 27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1632A>T	p.Arg544Ser	missense_variant	Exon 17 of 27		NP_001394094.1
RB1	NM_001407166.1	c.1632A>T	p.Arg544Ser	missense_variant	Exon 17 of 17		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1632A>T	p.Arg544Ser	missense_variant	Exon 17 of 27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.1632A>T	p.Arg544Ser	missense_variant	Exon 17 of 27			ENSP00000497193.1
RB1	ENST00000643064.1	c.129A>T	p.Arg43Ser	missense_variant	Exon 1 of 2			ENSP00000496005.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250028 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135058

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460442 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726358

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinoblastoma Uncertain:1

Aug 18, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals with RB1-related conditions. This variant is present in population databases (rs143948310, ExAC 0.01%). This sequence change replaces arginine with serine at codon 544 of the RB1 protein (p.Arg544Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D;.
Eigen	Benign	0.046
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.85	D;D
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.6	D;.
REVEL	Uncertain	0.52
Sift	Benign	0.078	T;.
Sift4G	Benign	0.12	T;.
Polyphen		0.36	B;.
Vest4		0.40
MutPred		0.72		Gain of catalytic residue at N541 (P = 9e-04);Gain of catalytic residue at N541 (P = 9e-04);
MVP		0.86
MPC		0.94
ClinPred		0.84	D
GERP RS		4.2
Varity_R		0.67
gMVP		0.62

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: rs143948310; hg19: chr13-48955516;