rs375751988

Variant names:

• chr13-48465334-C-A
• NM_000321.3:c.2455C>A

Your query was ambiguous. Multiple possible variants found:

• chr13-48465334-C-A
• chr13-48465334-C-G
• chr13-48465334-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000321.3(RB1):​c.2455C>A​(p.Leu819Met) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L819L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 28)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0920

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a region_of_interest Domain C; mediates interaction with E4F1 (size 157) in uniprot entity RB_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000321.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.2455C>A	p.Leu819Met	missense_variant	Exon 23 of 27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.2455C>A	p.Leu819Met	missense_variant	Exon 23 of 27		NP_001394094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.2455C>A	p.Leu819Met	missense_variant	Exon 23 of 27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.2455C>A	p.Leu819Met	missense_variant	Exon 23 of 27			ENSP00000497193.1
RB1	ENST00000643064.1	c.192+83891C>A		intron_variant	Intron 1 of 1			ENSP00000496005.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.4	L;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.43	N;.
REVEL	Uncertain	0.32
Sift	Benign	0.070	T;.
Sift4G	Benign	0.26	T;.
Polyphen		0.78	P;.
Vest4		0.28
MutPred		0.51		Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);
MVP		0.83
MPC		0.53
ClinPred		0.54	D
GERP RS		0.046
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.079
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.87		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.87		Position offset: -3
DS_DL_spliceai		0.23		Position offset: 34

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-49039470;