16-24562083-C-T

Position:

• chr16-24562083-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006910.5(RBBP6):​c.1211C>T​(p.Ser404Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBBP6 NM_006910.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.59

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]

RBBP6 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16415173).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBBP6	NM_006910.5	c.1211C>T	p.Ser404Phe	missense_variant	10/18	ENST00000319715.10	NP_008841.2
RBBP6	NM_018703.4	c.1211C>T	p.Ser404Phe	missense_variant	10/17		NP_061173.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBBP6	ENST00000319715.10	c.1211C>T	p.Ser404Phe	missense_variant	10/18	1	NM_006910.5	ENSP00000317872.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 22, 2022

DNA sequence analysis of the RBBP6 gene demonstrated a sequence change, c.1211C>T, in exon 10 that results in an amino acid change, p.Ser404Phe. This sequence change does not appear to have been previously described in individuals with RBBP6-related disorders and has also not been described in population databases such as ExAC and gnomAD. The p.Ser404Phe change affects a highly conserved amino acid residue located in a domain of the RBBP6 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ser404Phe substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Ser404Phe change remains unknown at this time. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	.;T;.;.;.
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D;D;D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.16	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	.;N;N;.;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.3	N;D;N;.;D
REVEL	Benign	0.069
Sift	Pathogenic	0.0	D;D;D;.;D
Sift4G	Uncertain	0.020	D;D;D;.;D
Polyphen		0.64, 0.76	.;P;P;.;P
Vest4		0.46, 0.41, 0.47
MutPred		0.15		.;Loss of glycosylation at S404 (P = 0.0032);Loss of glycosylation at S404 (P = 0.0032);.;Loss of glycosylation at S404 (P = 0.0032);
MVP		0.24
MPC		0.56
ClinPred		0.70	D
GERP RS		4.7
Varity_R		0.39
gMVP		0.55

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-24573404;