1-205101640-T-G

Variant names:

• chr1-205101640-T-G
• rs748242807
• NM_005057.4:c.592A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005057.4(RBBP5):​c.592A>C​(p.Thr198Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T198A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RBBP5 NM_005057.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.07
• Publications: 0 publications found

Genes affected

RBBP5 (HGNC:9888): (RB binding protein 5, histone lysine methyltransferase complex subunit) This gene encodes a ubiquitously expressed nuclear protein which belongs to a highly conserved subfamily of WD-repeat proteins. The encoded protein binds directly to retinoblastoma protein, which regulates cell proliferation. It interacts preferentially with the underphosphorylated retinoblastoma protein via the E1A-binding pocket B. Three alternatively spliced transcript variants that encode different protein isoforms have been described for this gene. [provided by RefSeq, Jul 2010]

RBBP5 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005057.4. 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
	RBBP5	NM_005057.4	MANE Select	c.592A>C	p.Thr198Pro	missense	Exon 6 of 14	NP_005048.2
	RBBP5	NM_001193272.2		c.592A>C	p.Thr198Pro	missense	Exon 6 of 14	NP_001180201.1	Q15291-2
	RBBP5	NM_001193273.2		c.211A>C	p.Thr71Pro	missense	Exon 6 of 14	NP_001180202.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBBP5	ENST00000264515.11	TSL:1 MANE Select	c.592A>C	p.Thr198Pro	missense	Exon 6 of 14	ENSP00000264515.6	Q15291-1
	RBBP5	ENST00000367164.1	TSL:1	c.592A>C	p.Thr198Pro	missense	Exon 6 of 14	ENSP00000356132.1	Q15291-2
	RBBP5	ENST00000861178.1		c.592A>C	p.Thr198Pro	missense	Exon 6 of 14	ENSP00000531237.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000412 AC: 5

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.073	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.1
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.14
Sift	Benign	0.042	D
Sift4G	Uncertain	0.048	D
Polyphen		0.96	D
Vest4		0.60
MutPred		0.40		Gain of glycosylation at T195 (P = 0.0736)
MVP		0.50
MPC		2.1
ClinPred		0.91	D
GERP RS		5.8
Varity_R		0.77
gMVP		0.62
Mutation Taster		=22/78	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs748242807; hg19: chr1-205070768;