NM_000321.3:c.1390-14A>T

Variant names:

• chr13-48380039-A-T
• rs9535023
• NM_000321.3:c.1390-14A>T

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.1390-14A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0546 in 1,242,656 control chromosomes in the GnomAD database, including 2,392 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (221 hom., cov: 29)
  • Exomes 𝑓: 0.056 (2171 hom.)
• Consequence: RB1 NM_000321.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.649
• Publications: 10 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

LOC112268118 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 13-48380039-A-T is Benign according to our data. Variant chr13-48380039-A-T is described in ClinVar as Benign. ClinVar VariationId is 167566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0736 is higher than 0.05.

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.1390-14A>T		intron	N/A	NP_000312.2	P06400
	RB1	NM_001407165.1		c.1390-14A>T		intron	N/A	NP_001394094.1	A0A3B3IS71
	RB1	NM_001407166.1		c.1390-14A>T		intron	N/A	NP_001394095.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.1390-14A>T		intron	N/A	ENSP00000267163.4	P06400
	RB1	ENST00000467505.6	TSL:1	n.*758-14A>T		intron	N/A	ENSP00000434702.1	Q92728
	RB1	ENST00000924352.1		c.1513-14A>T		intron	N/A	ENSP00000594411.1

Frequencies

GnomAD3 genomes AF: 0.0471 AC: 6973 AN: 148040 Hom.: 221 Cov.: 29

Gnomad AFR AF: 0.0120

Gnomad AMI AF: 0.0927

Gnomad AMR AF: 0.0458

Gnomad ASJ AF: 0.0305

Gnomad EAS AF: 0.000588

Gnomad SAS AF: 0.00909

Gnomad FIN AF: 0.0448

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0753

Gnomad OTH AF: 0.0541

GnomAD2 exomes AF: 0.0417 AC: 4720 AN: 113174 AF XY: 0.0410

Gnomad AFR exome AF: 0.00792

Gnomad AMR exome AF: 0.0260

Gnomad ASJ exome AF: 0.0322

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0573

Gnomad NFE exome AF: 0.0640

Gnomad OTH exome AF: 0.0426

GnomAD4 exome AF: 0.0556 AC: 60894 AN: 1094532 Hom.: 2171 Cov.: 19 AF XY: 0.0549 AC XY: 30092 AN XY: 547818

African (AFR) AF: 0.00764 AC: 176 AN: 23044

American (AMR) AF: 0.0306 AC: 637 AN: 20806

Ashkenazi Jewish (ASJ) AF: 0.0351 AC: 689 AN: 19602

East Asian (EAS) AF: 0.0000683 AC: 2 AN: 29274

South Asian (SAS) AF: 0.0106 AC: 655 AN: 62056

European-Finnish (FIN) AF: 0.0529 AC: 2143 AN: 40486

Middle Eastern (MID) AF: 0.0224 AC: 70 AN: 3124

European-Non Finnish (NFE) AF: 0.0639 AC: 54343 AN: 851064

Other (OTH) AF: 0.0483 AC: 2179 AN: 45076

GnomAD4 genome AF: 0.0470 AC: 6969 AN: 148124 Hom.: 221 Cov.: 29 AF XY: 0.0449 AC XY: 3238 AN XY: 72146

African (AFR) AF: 0.0120 AC: 488 AN: 40624

American (AMR) AF: 0.0457 AC: 681 AN: 14914

Ashkenazi Jewish (ASJ) AF: 0.0305 AC: 105 AN: 3448

East Asian (EAS) AF: 0.000589 AC: 3 AN: 5092

South Asian (SAS) AF: 0.00869 AC: 41 AN: 4720

European-Finnish (FIN) AF: 0.0448 AC: 404 AN: 9024

Middle Eastern (MID) AF: 0.0139 AC: 4 AN: 288

European-Non Finnish (NFE) AF: 0.0753 AC: 5049 AN: 67056

Other (OTH) AF: 0.0536 AC: 110 AN: 2052

Alfa AF: 0.0568 Hom.: 38

Bravo AF: 0.0471

Asia WGS AF: 0.0240 AC: 85 AN: 3464

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Retinoblastoma (6)
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.2
DANN	Benign	0.56
PhyloP100		0.65
Mutation Taster		=47/36	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
SpliceAI score (max)		0.020		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: rs9535023; hg19: chr13-48954175; COSMIC: COSV57303499;