1-32668257-A-T

Position:

• chr1-32668257-A-T

Variant summary

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

The NM_005610.3(RBBP4):​c.343A>T​(p.Ile115Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBBP4 NM_005610.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.30

Genes affected

RBBP4 (HGNC:9887): (RB binding protein 4, chromatin remodeling factor) This gene encodes a ubiquitously expressed nuclear protein which belongs to a highly conserved subfamily of WD-repeat proteins. It is present in protein complexes involved in histone acetylation and chromatin assembly. It is part of the Mi-2 complex which has been implicated in chromatin remodeling and transcriptional repression associated with histone deacetylation. This encoded protein is also part of co-repressor complexes, which is an integral component of transcriptional silencing. It is found among several cellular proteins that bind directly to retinoblastoma protein to regulate cell proliferation. This protein also seems to be involved in transcriptional repression of E2F-responsive genes. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2008]

RBBP4 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBBP4	NM_005610.3	c.343A>T	p.Ile115Phe	missense_variant	4/12	ENST00000373493.10	NP_005601.1
RBBP4	NM_001135255.2	c.340A>T	p.Ile114Phe	missense_variant	4/12		NP_001128727.1
RBBP4	NM_001135256.2	c.238A>T	p.Ile80Phe	missense_variant	4/12		NP_001128728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBBP4	ENST00000373493.10	c.343A>T	p.Ile115Phe	missense_variant	4/12	1	NM_005610.3	ENSP00000362592.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2023

The c.343A>T (p.I115F) alteration is located in exon 4 (coding exon 4) of the RBBP4 gene. This alteration results from a A to T substitution at nucleotide position 343, causing the isoleucine (I) at amino acid position 115 to be replaced by a phenylalanine (F). 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	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Benign	0.35	.;T;.;.;T
Eigen	Benign	-0.012
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Benign	0.0071	T
MetaRNN	Uncertain	0.48	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.2	.;L;L;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.2	D;D;D;D;D
REVEL	Benign	0.28
Sift	Benign	0.37	T;T;T;T;T
Sift4G	Benign	0.43	T;T;T;T;T
Polyphen		0.0020	B;B;.;.;.
Vest4		0.63
MutPred		0.46		.;Gain of methylation at K114 (P = 0.0373);Gain of methylation at K114 (P = 0.0373);.;.;
MVP		0.79
MPC		2.2
ClinPred		0.83	D
GERP RS		5.5
Varity_R		0.72
gMVP		0.91

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: chr1-33133858;