rs780722374

Variant names:

• chr16-24562002-C-T
• rs780722374
• NM_006910.5:c.1130C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_006910.5(RBBP6):​c.1130C>T​(p.Ser377Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000349 in 1,461,520 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: RBBP6 NM_006910.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.30
• Publications: 0 publications found

Genes affected

RBBP6 (HGNC:9889): (RB binding protein 6, ubiquitin ligase) The retinoblastoma tumor suppressor (pRB) protein binds with many other proteins. In various human cancers, pRB suppresses cellular proliferation and is inactivated. Cell cycle-dependent phosphorylation regulates the activity of pRB. This gene encodes a protein which binds to underphosphorylated but not phosphorylated pRB. Multiple alternatively spliced transcript variants that encode different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026003927).
• BS2: High AC in GnomAdExome4 at 51 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006910.5. 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
	RBBP6	NM_006910.5	MANE Select	c.1130C>T	p.Ser377Leu	missense	Exon 10 of 18	NP_008841.2
	RBBP6	NM_018703.4		c.1130C>T	p.Ser377Leu	missense	Exon 10 of 17	NP_061173.1	Q7Z6E9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBBP6	ENST00000319715.10	TSL:1 MANE Select	c.1130C>T	p.Ser377Leu	missense	Exon 10 of 18	ENSP00000317872.4	Q7Z6E9-1
	RBBP6	ENST00000348022.6	TSL:1	c.1130C>T	p.Ser377Leu	missense	Exon 10 of 17	ENSP00000316291.4	Q7Z6E9-2
	RBBP6	ENST00000381039.7	TSL:1	c.1130C>T	p.Ser377Leu	missense	Exon 10 of 11	ENSP00000370427.3	Q7Z6E9-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.000179 AC: 45 AN: 251304 AF XY: 0.000169

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000349 AC: 51 AN: 1461520 Hom.: 0 Cov.: 32 AF XY: 0.0000371 AC XY: 27 AN XY: 727116

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00110 AC: 49 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86250

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111690

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000682 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.000181 AC: 22

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	0.091
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		3.3
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.15
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.024	D
Polyphen		0.65	P
Vest4		0.28
MutPred		0.13		Loss of glycosylation at S377 (P = 0.005)
MVP		0.26
MPC		0.13
ClinPred		0.15	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.097
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs780722374; hg19: chr16-24573323;