chr20-36998838-G-A

Variant names:

• chr20-36998838-G-A
• rs368384666
• NM_002895.5:c.3128C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002895.5(RBL1):​c.3128C>T​(p.Ala1043Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000452 in 1,613,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. A1043D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: RBL1 NM_002895.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.07
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10364288).
• BS2: High AC in GnomAdExome4 at 70 AD gene.

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.3128C>T	p.Ala1043Val	missense	Exon 22 of 22	NP_002886.2
	RBL1	NM_001323281.2		c.1847C>T	p.Ala616Val	missense	Exon 21 of 21	NP_001310210.1
	RBL1	NM_001323282.2		c.1847C>T	p.Ala616Val	missense	Exon 22 of 22	NP_001310211.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBL1	ENST00000373664.8	TSL:1 MANE Select	c.3128C>T	p.Ala1043Val	missense	Exon 22 of 22	ENSP00000362768.3	P28749-1
	RBL1	ENST00000927851.1		c.2963C>T	p.Ala988Val	missense	Exon 21 of 21	ENSP00000597910.1
	RBL1	ENST00000927852.1		c.2522C>T	p.Ala841Val	missense	Exon 17 of 17	ENSP00000597911.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000875 AC: 22 AN: 251328 AF XY: 0.000133

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.0000479 AC: 70 AN: 1461006 Hom.: 0 Cov.: 30 AF XY: 0.0000702 AC XY: 51 AN XY: 726892

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.000615 AC: 53 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111328

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74450

African (AFR) AF: 0.00 AC: 0 AN: 41548

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000824 AC: 10

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.10	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.1
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.023	D
Polyphen		0.64	P
Vest4		0.085
MutPred		0.13		Gain of helix (P = 0.062)
MVP		0.90
MPC		0.36
ClinPred		0.22	T
GERP RS		4.9
Varity_R		0.21
gMVP		0.25
Mutation Taster		=97/3	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

dbSNP: rs368384666; hg19: chr20-35627241;