rs148980395

Variant names:

• chr13-48303954-C-T
• rs148980395
• NM_000321.3:c.42C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000321.3(RB1):​c.42C>T​(p.Ala14Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00302 in 1,503,378 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (11 hom.)
• Consequence: RB1 NM_000321.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.693
• Publications: 2 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-DT (HGNC:42778): (RB1 divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 13-48303954-C-T is Benign according to our data. Variant chr13-48303954-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 237673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.693 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00155 (230/148840) while in subpopulation NFE AF = 0.00294 (200/67934). AF 95% confidence interval is 0.00261. There are 0 homozygotes in GnomAd4. There are 98 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 230 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	NM_000321.3	MANE Select	c.42C>T	p.Ala14Ala	synonymous	Exon 1 of 27	NP_000312.2
	RB1	NM_001407165.1		c.42C>T	p.Ala14Ala	synonymous	Exon 1 of 27	NP_001394094.1
	RB1	NM_001407166.1		c.42C>T	p.Ala14Ala	synonymous	Exon 1 of 17	NP_001394095.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.42C>T	p.Ala14Ala	synonymous	Exon 1 of 27	ENSP00000267163.4
	RB1	ENST00000467505.6	TSL:1	n.42C>T		non_coding_transcript_exon	Exon 1 of 22	ENSP00000434702.1
	RB1	ENST00000924352.1		c.42C>T	p.Ala14Ala	synonymous	Exon 1 of 28	ENSP00000594411.1

Frequencies

GnomAD3 genomes AF: 0.00155 AC: 230 AN: 148746 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00294

Gnomad OTH AF: 0.000966

GnomAD2 exomes AF: 0.00145 AC: 152 AN: 104982 AF XY: 0.00131

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.0000465

Gnomad ASJ exome AF: 0.000140

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000176

Gnomad NFE exome AF: 0.00372

Gnomad OTH exome AF: 0.00124

GnomAD4 exome AF: 0.00319 AC: 4316 AN: 1354538 Hom.: 11 Cov.: 31 AF XY: 0.00305 AC XY: 2041 AN XY: 668374

African (AFR) AF: 0.000623 AC: 16 AN: 25678

American (AMR) AF: 0.0000908 AC: 3 AN: 33056

Ashkenazi Jewish (ASJ) AF: 0.000165 AC: 4 AN: 24192

East Asian (EAS) AF: 0.00 AC: 0 AN: 32396

South Asian (SAS) AF: 0.0000131 AC: 1 AN: 76606

European-Finnish (FIN) AF: 0.000412 AC: 14 AN: 34004

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4018

European-Non Finnish (NFE) AF: 0.00392 AC: 4190 AN: 1068328

Other (OTH) AF: 0.00156 AC: 88 AN: 56260

GnomAD4 genome AF: 0.00155 AC: 230 AN: 148840 Hom.: 0 Cov.: 32 AF XY: 0.00135 AC XY: 98 AN XY: 72804

African (AFR) AF: 0.000650 AC: 25 AN: 38448

American (AMR) AF: 0.000132 AC: 2 AN: 15148

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00294 AC: 200 AN: 67934

Other (OTH) AF: 0.000956 AC: 2 AN: 2092

Alfa AF: 0.00206 Hom.: 0

Bravo AF: 0.00158

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	7.6
DANN	Benign	0.88
PhyloP100		-0.69
PromoterAI		-0.0080	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Mutation Taster		=100/0	polymorphism

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: rs148980395; hg19: chr13-48878090; COSMIC: COSV57300001; COSMIC: COSV57300001;