rs4151580

chr13-48453505-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000321.3(RB1):c.1814+394G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0168 in 152,310 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.017 (48 hom., cov: 32)
• Consequence: RB1 NM_000321.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.76

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0168 (2560/152310) while in subpopulation AMR AF= 0.0436 (666/15292). AF 95% confidence interval is 0.0408. There are 48 homozygotes in gnomad4. There are 1245 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 2559 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RB1	NM_000321.3	c.1814+394G>A		intron_variant		ENST00000267163.6
RB1	NM_001407165.1	c.1814+394G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RB1	ENST00000267163.6	c.1814+394G>A		intron_variant		1	NM_000321.3	P1
RB1	ENST00000643064.1	c.194+72062G>A		intron_variant
RB1	ENST00000650461.1	c.1814+394G>A		intron_variant
RB1	ENST00000480491.1	n.513+394G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0168 AC: 2559 AN: 152192 Hom.: 48 Cov.: 32

Gnomad AFR AF: 0.00473

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0434

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.0148

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0212

Gnomad OTH AF: 0.0110

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0168 AC: 2560 AN: 152310 Hom.: 48 Cov.: 32 AF XY: 0.0167 AC XY: 1245 AN XY: 74474

Gnomad4 AFR AF: 0.00471

Gnomad4 AMR AF: 0.0436

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00829

Gnomad4 FIN AF: 0.0148

Gnomad4 NFE AF: 0.0212

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0195 Hom.: 10

Bravo AF: 0.0180

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	11
Dann	Benign	0.64

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: rs4151580; hg19: chr13-49027641;