rs7329938

Variant names:

• chr13-48357843-T-C
• rs7329938
• NM_000321.3:c.608-2174T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000321.3(RB1):​c.608-2174T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0782 in 152,234 control chromosomes in the GnomAD database, including 637 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.078 (637 hom., cov: 32)
• Consequence: RB1 NM_000321.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.198
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.608-2174T>C		intron_variant	Intron 6 of 26	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.608-2174T>C		intron_variant	Intron 6 of 26		NP_001394094.1
RB1	NM_001407166.1	c.608-2174T>C		intron_variant	Intron 6 of 16		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.608-2174T>C		intron_variant	Intron 6 of 26	1	NM_000321.3	ENSP00000267163.4

Frequencies

GnomAD3 genomes AF: 0.0783 AC: 11911 AN: 152116 Hom.: 638 Cov.: 32

Gnomad AFR AF: 0.0204

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.0647

Gnomad ASJ AF: 0.0942

Gnomad EAS AF: 0.0337

Gnomad SAS AF: 0.144

Gnomad FIN AF: 0.0731

Gnomad MID AF: 0.0764

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.0833

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0782 AC: 11903 AN: 152234 Hom.: 637 Cov.: 32 AF XY: 0.0774 AC XY: 5758 AN XY: 74430

African (AFR) AF: 0.0204 AC: 847 AN: 41582

American (AMR) AF: 0.0646 AC: 985 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.0942 AC: 327 AN: 3470

East Asian (EAS) AF: 0.0334 AC: 173 AN: 5178

South Asian (SAS) AF: 0.144 AC: 695 AN: 4826

European-Finnish (FIN) AF: 0.0731 AC: 776 AN: 10620

Middle Eastern (MID) AF: 0.0753 AC: 22 AN: 292

European-Non Finnish (NFE) AF: 0.114 AC: 7772 AN: 67984

Other (OTH) AF: 0.0819 AC: 173 AN: 2112

Alfa AF: 0.0941 Hom.: 762

Bravo AF: 0.0747

Asia WGS AF: 0.0920 AC: 317 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.6
DANN	Benign	0.91
PhyloP100		0.20
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: rs7329938; hg19: chr13-48931979;