16-24561938-C-A

Variant names:

• chr16-24561938-C-A
• NM_006910.5:c.1066C>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_006910.5(RBBP6):​c.1066C>A​(p.Pro356Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,572 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: RBBP6 NM_006910.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.12

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

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24346301).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBBP6	NM_006910.5	c.1066C>A	p.Pro356Thr	missense_variant	Exon 10 of 18	ENST00000319715.10	NP_008841.2
RBBP6	NM_018703.4	c.1066C>A	p.Pro356Thr	missense_variant	Exon 10 of 17		NP_061173.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBBP6	ENST00000319715.10	c.1066C>A	p.Pro356Thr	missense_variant	Exon 10 of 18	1	NM_006910.5	ENSP00000317872.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461572 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727128

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1066C>A (p.P356T) alteration is located in exon 10 (coding exon 10) of the RBBP6 gene. This alteration results from a C to A substitution at nucleotide position 1066, causing the proline (P) at amino acid position 356 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	0.0025	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	.;T;.;.;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.88	D;D;D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.24	T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	0.97	.;L;L;.;L
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.1	D;D;D;.;D
REVEL	Benign	0.21
Sift	Benign	0.048	D;D;D;.;D
Sift4G	Uncertain	0.016	D;D;D;.;D
Polyphen		1.0	.;D;D;.;D
Vest4		0.44, 0.43, 0.78
MutPred		0.20		.;Loss of loop (P = 0.0153);Loss of loop (P = 0.0153);.;Loss of loop (P = 0.0153);
MVP		0.45
MPC		0.22
ClinPred		0.91	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.69

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: chr16-24573259;