20-18489806-T-G

Variant names:

• chr20-18489806-T-G
• NM_006606.3:c.519A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006606.3(RBBP9):​c.519A>C​(p.Glu173Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: 6.8e-7 (0 hom.)
• Consequence: RBBP9 NM_006606.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.662
• Publications: 0 publications found

Genes affected

RBBP9 (HGNC:9892): (RB binding protein 9, serine hydrolase) The protein encoded by this gene is a retinoblastoma binding protein that may play a role in the regulation of cell proliferation and differentiation. Two alternatively spliced transcript variants of this gene with identical predicted protein products have been reported, one of which is a nonsense-mediated decay candidate. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3776172).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006606.3. 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
	RBBP9	NM_006606.3	MANE Select	c.519A>C	p.Glu173Asp	missense	Exon 5 of 5	NP_006597.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBBP9	ENST00000337227.9	TSL:1 MANE Select	c.519A>C	p.Glu173Asp	missense	Exon 5 of 5	ENSP00000336866.4	O75884-1
	RBBP9	ENST00000966865.1		c.513A>C	p.Glu171Asp	missense	Exon 5 of 5	ENSP00000636924.1
	RBBP9	ENST00000491835.1	TSL:2	n.483A>C		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461604 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727058

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111786

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

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	0.24
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Benign	0.021
Eigen_PC	Benign	-0.040
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.66
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.24
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.022	D
Polyphen		0.97	D
Vest4		0.44
MutPred		0.65		Loss of sheet (P = 0.0181)
MVP		0.31
MPC		0.18
ClinPred		0.80	D
GERP RS		1.5
Varity_R		0.59
gMVP		0.36
Mutation Taster		=79/21	polymorphism

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

hg19: chr20-18470450;