13-48459611-G-A

Variant names:

• chr13-48459611-G-A
• rs198580
• NM_000321.3:c.1961-77G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000321.3(RB1):​c.1961-77G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.958 in 1,449,372 control chromosomes in the GnomAD database, including 668,725 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (61471 hom., cov: 32)
  • Exomes 𝑓: 0.97 (607254 hom.)
• Consequence: RB1 NM_000321.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.292
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 13-48459611-G-A is Benign according to our data. Variant chr13-48459611-G-A is described in CliVar as Benign. Clinvar id is 1222742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48459611-G-A is described in CliVar as Benign. Clinvar id is 1222742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48459611-G-A is described in CliVar as Benign. Clinvar id is 1222742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48459611-G-A is described in CliVar as Benign. Clinvar id is 1222742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48459611-G-A is described in CliVar as Benign. Clinvar id is 1222742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48459611-G-A is described in CliVar as Benign. Clinvar id is 1222742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48459611-G-A is described in CliVar as Benign. Clinvar id is 1222742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48459611-G-A is described in CliVar as Benign. Clinvar id is 1222742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48459611-G-A is described in CliVar as Benign. Clinvar id is 1222742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48459611-G-A is described in CliVar as Benign. Clinvar id is 1222742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48459611-G-A is described in CliVar as Benign. Clinvar id is 1222742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48459611-G-A is described in CliVar as Benign. Clinvar id is 1222742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.1961-77G>A		intron_variant	Intron 19 of 26	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1961-77G>A		intron_variant	Intron 19 of 26		NP_001394094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1961-77G>A		intron_variant	Intron 19 of 26	1	NM_000321.3	ENSP00000267163.4

Frequencies

GnomAD3 genomes AF: 0.890 AC: 135268 AN: 152068 Hom.: 61450 Cov.: 32

Gnomad AFR AF: 0.681

Gnomad AMI AF: 0.992

Gnomad AMR AF: 0.920

Gnomad ASJ AF: 0.933

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.953

Gnomad FIN AF: 0.994

Gnomad MID AF: 0.917

Gnomad NFE AF: 0.976

Gnomad OTH AF: 0.908

GnomAD4 exome AF: 0.966 AC: 1253427 AN: 1297186 Hom.: 607254 AF XY: 0.966 AC XY: 631970 AN XY: 653924

African (AFR) AF: 0.670 AC: 20143 AN: 30044

American (AMR) AF: 0.941 AC: 41842 AN: 44470

Ashkenazi Jewish (ASJ) AF: 0.929 AC: 23324 AN: 25116

East Asian (EAS) AF: 0.998 AC: 38773 AN: 38834

South Asian (SAS) AF: 0.953 AC: 78814 AN: 82694

European-Finnish (FIN) AF: 0.990 AC: 52634 AN: 53176

Middle Eastern (MID) AF: 0.908 AC: 4963 AN: 5466

European-Non Finnish (NFE) AF: 0.978 AC: 940889 AN: 962520

Other (OTH) AF: 0.949 AC: 52045 AN: 54866

GnomAD4 genome AF: 0.889 AC: 135347 AN: 152186 Hom.: 61471 Cov.: 32 AF XY: 0.893 AC XY: 66468 AN XY: 74414

African (AFR) AF: 0.681 AC: 28231 AN: 41444

American (AMR) AF: 0.920 AC: 14087 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.933 AC: 3239 AN: 3472

East Asian (EAS) AF: 0.997 AC: 5158 AN: 5176

South Asian (SAS) AF: 0.953 AC: 4598 AN: 4824

European-Finnish (FIN) AF: 0.994 AC: 10547 AN: 10616

Middle Eastern (MID) AF: 0.921 AC: 269 AN: 292

European-Non Finnish (NFE) AF: 0.976 AC: 66394 AN: 68030

Other (OTH) AF: 0.909 AC: 1921 AN: 2114

Alfa AF: 0.936 Hom.: 11904

Bravo AF: 0.875

Asia WGS AF: 0.947 AC: 3296 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

Significance: 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	-0.91
CADD	Benign	1.9
DANN	Benign	0.39
PhyloP100		0.29
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: rs198580; hg19: chr13-49033747;