chr13-48464989-C-G

Variant names:

• chr13-48464989-C-G
• rs765386327
• NM_000321.3:c.2212-9C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_000321.3(RB1):​c.2212-9C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. 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. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0015 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RB1 NM_000321.3 intron
• Scores: Splicing: ADA: 0.0003006
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0290
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 13-48464989-C-G is Benign according to our data. Variant chr13-48464989-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1608637.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.2212-9C>G		intron_variant	Intron 21 of 26	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.2212-9C>G		intron_variant	Intron 21 of 26		NP_001394094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.2212-9C>G		intron_variant	Intron 21 of 26	1	NM_000321.3	ENSP00000267163.4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 54892 Hom.: 0 Cov.: 0

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: 0.00146 AC: 780 AN: 533486 Hom.: 0 Cov.: 16 AF XY: 0.00129 AC XY: 365 AN XY: 282072

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

African (AFR) AF: 0.000606 AC: 8 AN: 13204

American (AMR) AF: 0.000211 AC: 5 AN: 23704

Ashkenazi Jewish (ASJ) AF: 0.000626 AC: 8 AN: 12776

East Asian (EAS) AF: 0.000460 AC: 10 AN: 21722

South Asian (SAS) AF: 0.000292 AC: 13 AN: 44542

European-Finnish (FIN) AF: 0.000564 AC: 20 AN: 35442

Middle Eastern (MID) AF: 0.00290 AC: 5 AN: 1722

European-Non Finnish (NFE) AF: 0.00191 AC: 683 AN: 357110

Other (OTH) AF: 0.00120 AC: 28 AN: 23264

⚠️ 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;AS_VQSR AF: 0.00 AC: 0 AN: 54918 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 26044

African (AFR) AF: 0.00 AC: 0 AN: 15178

American (AMR) AF: 0.00 AC: 0 AN: 5124

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1412

East Asian (EAS) AF: 0.00 AC: 0 AN: 1870

South Asian (SAS) AF: 0.00 AC: 0 AN: 1402

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2130

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 90

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 26548

Other (OTH) AF: 0.00 AC: 0 AN: 708

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinoblastoma Benign:1

Nov 07, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	15
DANN	Benign	0.51
PhyloP100		-0.029

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00030
dbscSNV1_RF	Benign	0.10
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: rs765386327; hg19: chr13-49039125;