13-48464992-C-A

Variant names:

• chr13-48464992-C-A
• rs776162179
• NM_000321.3:c.2212-6C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000321.3(RB1):​c.2212-6C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000808 in 618,822 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 18)
  • Exomes 𝑓: 0.0000081 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RB1 NM_000321.3 splice_region, intron
• Scores: Splicing: ADA: 0.0004990
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.312
• Publications: 0 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• retinoblastoma

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

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000321.3. 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
	RB1	NM_000321.3	MANE Select	c.2212-6C>A		splice_region intron	N/A	NP_000312.2	P06400
	RB1	NM_001407165.1		c.2212-6C>A		splice_region intron	N/A	NP_001394094.1	A0A3B3IS71

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.2212-6C>A		splice_region intron	N/A	ENSP00000267163.4	P06400
	RB1	ENST00000467505.6	TSL:1	n.*1580-6C>A		splice_region intron	N/A	ENSP00000434702.1	Q92728
	RB1	ENST00000924352.1		c.2335-6C>A		splice_region intron	N/A	ENSP00000594411.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 74172 Hom.: 0 Cov.: 18

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000808 AC: 5 AN: 618822 Hom.: 0 Cov.: 25 AF XY: 0.0000125 AC XY: 4 AN XY: 320340

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 21396

American (AMR) AF: 0.00 AC: 0 AN: 26574

Ashkenazi Jewish (ASJ) AF: 0.0000759 AC: 1 AN: 13170

East Asian (EAS) AF: 0.00 AC: 0 AN: 20390

South Asian (SAS) AF: 0.00 AC: 0 AN: 43104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1936

European-Non Finnish (NFE) AF: 0.00000931 AC: 4 AN: 429570

Other (OTH) AF: 0.00 AC: 0 AN: 26430

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 74172 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 34080

African (AFR) AF: 0.00 AC: 0 AN: 28122

American (AMR) AF: 0.00 AC: 0 AN: 4860

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1766

East Asian (EAS) AF: 0.00 AC: 0 AN: 2190

South Asian (SAS) AF: 0.00 AC: 0 AN: 2318

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1954

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 70

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 31554

Other (OTH) AF: 0.00 AC: 0 AN: 928

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	11
DANN	Benign	0.41
PhyloP100		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00050
dbscSNV1_RF	Benign	0.11
SpliceAI score (max)		0.010		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: rs776162179; hg19: chr13-49039128;