NM_000321.3:c.1632A>G

Variant names:

• chr13-48381380-A-G
• rs143948310
• NM_000321.3:c.1632A>G

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.1632A>G​(p.Arg544Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000397 in 1,612,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: RB1 NM_000321.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.75
• 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 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 13-48381380-A-G is Benign according to our data. Variant chr13-48381380-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 416489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.75 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00221 (336/152368) while in subpopulation AFR AF = 0.00777 (323/41588). AF 95% confidence interval is 0.00707. There are 0 homozygotes in GnomAd4. There are 167 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 336 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.1632A>G	p.Arg544Arg	synonymous	Exon 17 of 27	NP_000312.2	P06400
	RB1	NM_001407165.1		c.1632A>G	p.Arg544Arg	synonymous	Exon 17 of 27	NP_001394094.1	A0A3B3IS71
	RB1	NM_001407166.1		c.1632A>G	p.Arg544Arg	synonymous	Exon 17 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.1632A>G	p.Arg544Arg	synonymous	Exon 17 of 27	ENSP00000267163.4	P06400
	RB1	ENST00000467505.6	TSL:1	n.*1000A>G		non_coding_transcript_exon	Exon 12 of 22	ENSP00000434702.1	Q92728
	RB1	ENST00000467505.6	TSL:1	n.*1000A>G		3_prime_UTR	Exon 12 of 22	ENSP00000434702.1	Q92728

Frequencies

GnomAD3 genomes AF: 0.00221 AC: 336 AN: 152250 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00779

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

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: 0.00143

GnomAD2 exomes AF: 0.000536 AC: 134 AN: 250028 AF XY: 0.000415

Gnomad AFR exome AF: 0.00757

Gnomad AMR exome AF: 0.000262

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000208 AC: 304 AN: 1460442 Hom.: 0 Cov.: 32 AF XY: 0.000169 AC XY: 123 AN XY: 726358

African (AFR) AF: 0.00754 AC: 252 AN: 33432

American (AMR) AF: 0.000269 AC: 12 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39554

South Asian (SAS) AF: 0.00 AC: 0 AN: 86032

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000261 AC: 29 AN: 1111218

Other (OTH) AF: 0.000182 AC: 11 AN: 60346

GnomAD4 genome AF: 0.00221 AC: 336 AN: 152368 Hom.: 0 Cov.: 32 AF XY: 0.00224 AC XY: 167 AN XY: 74514

African (AFR) AF: 0.00777 AC: 323 AN: 41588

American (AMR) AF: 0.000653 AC: 10 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00114 Hom.: 0

Bravo AF: 0.00232

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Retinoblastoma (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	not provided (1)
-	-	1	RB1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	14
DANN	Benign	0.69
PhyloP100		1.7
PromoterAI		0.0034	Neutral
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: rs143948310; hg19: chr13-48955516;