NM_000321.3:c.1814+394G>A

Variant names:

• chr13-48453505-G-A
• rs4151580
• NM_000321.3:c.1814+394G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 5 publications found

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]

RB1 Gene-Disease associations (from GenCC):

• hereditary retinoblastoma

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
• retinoblastoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• melanoma

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2560 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.1814+394G>A		intron_variant	Intron 18 of 26	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1814+394G>A		intron_variant	Intron 18 of 26		NP_001394094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1814+394G>A		intron_variant	Intron 18 of 26	1	NM_000321.3	ENSP00000267163.4

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

African (AFR) AF: 0.00471 AC: 196 AN: 41574

American (AMR) AF: 0.0436 AC: 666 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.00829 AC: 40 AN: 4828

European-Finnish (FIN) AF: 0.0148 AC: 157 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0212 AC: 1439 AN: 68018

Other (OTH) AF: 0.0109 AC: 23 AN: 2114

Alfa AF: 0.0197 Hom.: 19

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
PhyloP100		1.8
Mutation Taster		=100/0	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: rs4151580; hg19: chr13-49027641;