NM_000321.3:c.1695+2737C>T

Variant names:

• chr13-48384180-C-T
• rs427686
• NM_000321.3:c.1695+2737C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000321.3(RB1):​c.1695+2737C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.782 in 152,064 control chromosomes in the GnomAD database, including 52,215 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 0.78 (52215 hom., cov: 32)
• Consequence: RB1 NM_000321.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.228
• Publications: 4 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=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.964 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.1695+2737C>T		intron_variant	Intron 17 of 26	ENST00000267163.6	NP_000312.2
RB1	NM_001407166.1	c.*2725C>T		3_prime_UTR_variant	Exon 17 of 17		NP_001394095.1
RB1	NM_001407165.1	c.1695+2737C>T		intron_variant	Intron 17 of 26		NP_001394094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1695+2737C>T		intron_variant	Intron 17 of 26	1	NM_000321.3	ENSP00000267163.4

Frequencies

GnomAD3 genomes AF: 0.782 AC: 118854 AN: 151948 Hom.: 52223 Cov.: 32

Gnomad AFR AF: 0.344

Gnomad AMI AF: 0.992

Gnomad AMR AF: 0.878

Gnomad ASJ AF: 0.920

Gnomad EAS AF: 0.867

Gnomad SAS AF: 0.904

Gnomad FIN AF: 0.974

Gnomad MID AF: 0.867

Gnomad NFE AF: 0.971

Gnomad OTH AF: 0.816

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

GnomAD4 genome AF: 0.782 AC: 118854 AN: 152064 Hom.: 52215 Cov.: 32 AF XY: 0.787 AC XY: 58512 AN XY: 74338

African (AFR) AF: 0.343 AC: 14227 AN: 41428

American (AMR) AF: 0.878 AC: 13410 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.920 AC: 3190 AN: 3468

East Asian (EAS) AF: 0.866 AC: 4485 AN: 5178

South Asian (SAS) AF: 0.905 AC: 4371 AN: 4832

European-Finnish (FIN) AF: 0.974 AC: 10334 AN: 10608

Middle Eastern (MID) AF: 0.871 AC: 256 AN: 294

European-Non Finnish (NFE) AF: 0.971 AC: 65970 AN: 67968

Other (OTH) AF: 0.810 AC: 1708 AN: 2108

Alfa AF: 0.841 Hom.: 7565

Bravo AF: 0.755

Asia WGS AF: 0.815 AC: 2823 AN: 3462

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.38
DANN	Benign	0.44
PhyloP100		-0.23
Mutation Taster		=100/0	polymorphism (auto)

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: rs427686; hg19: chr13-48958316;