chr16-24561956-A-G

Variant names:

• chr16-24561956-A-G
• rs1027411575
• NM_006910.5:c.1084A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006910.5(RBBP6):​c.1084A>G​(p.Ile362Val) 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RBBP6 NM_006910.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.954
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06719679).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBBP6	NM_006910.5	c.1084A>G	p.Ile362Val	missense_variant	Exon 10 of 18	ENST00000319715.10	NP_008841.2
RBBP6	NM_018703.4	c.1084A>G	p.Ile362Val	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.1084A>G	p.Ile362Val	missense_variant	Exon 10 of 18	1	NM_006910.5	ENSP00000317872.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1084A>G (p.I362V) alteration is located in exon 10 (coding exon 10) of the RBBP6 gene. This alteration results from a A to G substitution at nucleotide position 1084, causing the isoleucine (I) at amino acid position 362 to be replaced by a valine (V). 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	Benign	0.062
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.063	.;T;.;.;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.82	T;T;T;T;T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.067	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	.;N;N;.;N
PhyloP100		0.95
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.13	N;N;N;.;N
REVEL	Benign	0.042
Sift	Uncertain	0.018	D;D;D;.;D
Sift4G	Benign	0.48	T;T;T;.;T
Polyphen		0.039, 0.038, 0.065	.;B;B;.;B
Vest4		0.12, 0.095, 0.13
MVP		0.22
MPC		0.12
ClinPred		0.43	T
GERP RS		4.9
Varity_R		0.048
gMVP		0.47

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: rs1027411575; hg19: chr16-24573277;