20-37003817-C-T

Variant names:

• chr20-37003817-C-T
• NM_002895.5:c.2921G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002895.5(RBL1):​c.2921G>A​(p.Gly974Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RBL1 NM_002895.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.40
• Publications: 0 publications found

Genes affected

RBL1 (HGNC:9893): (RB transcriptional corepressor like 1) The protein encoded by this gene is similar in sequence and possibly function to the product of the retinoblastoma 1 (RB1) gene. The RB1 gene product is a tumor suppressor protein that appears to be involved in cell cycle regulation, as it is phosphorylated in the S to M phase transition and is dephosphorylated in the G1 phase of the cell cycle. Both the RB1 protein and the product of this gene can form a complex with adenovirus E1A protein and SV40 large T-antigen, with the SV40 large T-antigen binding only to the unphosphorylated form of each protein. In addition, both proteins can inhibit the transcription of cell cycle genes containing E2F binding sites in their promoters. Due to the sequence and biochemical similarities with the RB1 protein, it is thought that the protein encoded by this gene may also be a tumor suppressor. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23215273).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002895.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBL1	NM_002895.5	MANE Select	c.2921G>A	p.Gly974Asp	missense	Exon 21 of 22	NP_002886.2
	RBL1	NM_183404.4		c.2921G>A	p.Gly974Asp	missense	Exon 21 of 21	NP_899662.1	P28749-2
	RBL1	NM_001323281.2		c.1640G>A	p.Gly547Asp	missense	Exon 20 of 21	NP_001310210.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBL1	ENST00000373664.8	TSL:1 MANE Select	c.2921G>A	p.Gly974Asp	missense	Exon 21 of 22	ENSP00000362768.3	P28749-1
	RBL1	ENST00000344359.7	TSL:1	c.2921G>A	p.Gly974Asp	missense	Exon 21 of 21	ENSP00000343646.3	P28749-2
	RBL1	ENST00000927852.1		c.2315G>A	p.Gly772Asp	missense	Exon 16 of 17	ENSP00000597911.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		3.4
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.086
Sift	Benign	0.19	T
Sift4G	Benign	0.21	T
Polyphen		0.61	P
Vest4		0.34
MutPred		0.24		Gain of ubiquitination at K970 (P = 0.028)
MVP		0.82
MPC		0.68
ClinPred		0.84	D
GERP RS		4.0
Varity_R		0.16
gMVP		0.28
Mutation Taster		=92/8	polymorphism

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

hg19: chr20-35632220;