chr1-32668245-G-A

Position:

• chr1-32668245-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005610.3(RBBP4):​c.331G>A​(p.Val111Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,236 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RBBP4 NM_005610.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.97

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32980585).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBBP4	NM_005610.3	c.331G>A	p.Val111Ile	missense_variant	4/12	ENST00000373493.10	NP_005601.1
RBBP4	NM_001135255.2	c.328G>A	p.Val110Ile	missense_variant	4/12		NP_001128727.1
RBBP4	NM_001135256.2	c.226G>A	p.Val76Ile	missense_variant	4/12		NP_001128728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBBP4	ENST00000373493.10	c.331G>A	p.Val111Ile	missense_variant	4/12	1	NM_005610.3	ENSP00000362592.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460236 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726372

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: 9.00e-7

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 25, 2024

The c.331G>A (p.V111I) alteration is located in exon 4 (coding exon 4) of the RBBP4 gene. This alteration results from a G to A substitution at nucleotide position 331, causing the valine (V) at amino acid position 111 to be replaced by an isoleucine (I). 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	0.17
BayesDel_addAF	Benign	0.0085	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.095	.;T;.;.;T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.33	T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.1	.;L;L;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.71	N;N;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.30	T;T;T;T;T
Sift4G	Benign	0.43	T;T;T;T;T
Polyphen		0.0	B;B;.;.;.
Vest4		0.50
MutPred		0.31		.;Loss of sheet (P = 0.0025);Loss of sheet (P = 0.0025);.;.;
MVP		0.66
MPC		1.3
ClinPred		0.65	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.52

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: chr1-33133846;