13-48364952-C-T

Variant names:

• chr13-48364952-C-T
• rs183898408
• NM_000321.3:c.920C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000321.3(RB1):​c.920C>T​(p.Thr307Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,571,430 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T307A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00087 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (7 hom.)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:14 O:1
• Conservation: PhyloP100: 2.94
• Publications: 22 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

LOC112268118 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010866463).
• BP6: Variant 13-48364952-C-T is Benign according to our data. Variant chr13-48364952-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 135125.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000868 (132/152082) while in subpopulation SAS AF = 0.00374 (18/4810). AF 95% confidence interval is 0.00242. There are 0 homozygotes in GnomAd4. There are 82 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 132 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	NM_000321.3	MANE Select	c.920C>T	p.Thr307Ile	missense	Exon 9 of 27	NP_000312.2
	RB1	NM_001407165.1		c.920C>T	p.Thr307Ile	missense	Exon 9 of 27	NP_001394094.1
	RB1	NM_001407166.1		c.920C>T	p.Thr307Ile	missense	Exon 9 of 17	NP_001394095.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.920C>T	p.Thr307Ile	missense	Exon 9 of 27	ENSP00000267163.4
	RB1	ENST00000467505.6	TSL:1	n.*288C>T		non_coding_transcript_exon	Exon 4 of 22	ENSP00000434702.1
	RB1	ENST00000467505.6	TSL:1	n.*288C>T		3_prime_UTR	Exon 4 of 22	ENSP00000434702.1

Frequencies

GnomAD3 genomes AF: 0.000869 AC: 132 AN: 151964 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00374

Gnomad FIN AF: 0.000379

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000853

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00131 AC: 260 AN: 197864 AF XY: 0.00164

Gnomad AFR exome AF: 0.0000894

Gnomad AMR exome AF: 0.00117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000362

Gnomad NFE exome AF: 0.00118

Gnomad OTH exome AF: 0.000586

GnomAD4 exome AF: 0.00113 AC: 1607 AN: 1419348 Hom.: 7 Cov.: 30 AF XY: 0.00129 AC XY: 907 AN XY: 702842

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

African (AFR) AF: 0.0000938 AC: 3 AN: 31966

American (AMR) AF: 0.00107 AC: 45 AN: 42070

Ashkenazi Jewish (ASJ) AF: 0.0000790 AC: 2 AN: 25330

East Asian (EAS) AF: 0.0000266 AC: 1 AN: 37622

South Asian (SAS) AF: 0.00462 AC: 378 AN: 81792

European-Finnish (FIN) AF: 0.000395 AC: 20 AN: 50620

Middle Eastern (MID) AF: 0.00165 AC: 9 AN: 5444

European-Non Finnish (NFE) AF: 0.00103 AC: 1115 AN: 1086192

Other (OTH) AF: 0.000583 AC: 34 AN: 58312

⚠️ 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 AF: 0.000868 AC: 132 AN: 152082 Hom.: 0 Cov.: 32 AF XY: 0.00110 AC XY: 82 AN XY: 74342

African (AFR) AF: 0.000121 AC: 5 AN: 41476

American (AMR) AF: 0.00294 AC: 45 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00374 AC: 18 AN: 4810

European-Finnish (FIN) AF: 0.000379 AC: 4 AN: 10552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000853 AC: 58 AN: 67992

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00108 Hom.: 1

Bravo AF: 0.000861

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000467 AC: 2

ESP6500EA AF: 0.000943 AC: 8

ExAC AF: 0.000951 AC: 112

Asia WGS AF: 0.00231 AC: 8 AN: 3472

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not specified (6)
-	-	5	Retinoblastoma (5)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.040
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	0.55	N
PhyloP100		2.9
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.45
Sift	Benign	0.17	T
Sift4G	Benign	0.16	T
Polyphen		0.029	B
Vest4		0.72
MVP		0.93
MPC		0.55
ClinPred		0.0064	T
GERP RS		5.6
Varity_R		0.25
gMVP		0.40
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		0.0
SpliceAI score (max)		0.050		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: rs183898408; hg19: chr13-48939088; COSMIC: COSV57313105;