3-9734381-G-A

Position:

• chr3-9734381-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The ENST00000383829.7(BRPF1):​c.241G>A​(p.Val81Ile) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRPF1 ENST00000383829.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.60

Genes affected

BRPF1 (HGNC:14255): (bromodomain and PHD finger containing 1) This gene encodes a bromodomain, PHD finger and chromo/Tudor-related Pro-Trp-Trp-Pro (PWWP) domain containing protein. The encoded protein is a component of the MOZ/MORF histone acetyltransferase complexes which function as a transcriptional regulators. This protein binds to the catalytic MYST domains of the MOZ and MORF proteins and may play a role in stimulating acetyltransferase and transcriptional activity of the complex. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), BRPF1. . Gene score misZ 3.8305 (greater than the threshold 3.09). Trascript score misZ 4.9876 (greater than threshold 3.09). GenCC has associacion of gene with intellectual developmental disorder with dysmorphic facies and ptosis.
• BP4: Computational evidence support a benign effect (MetaRNN=0.053417206).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRPF1	NM_001003694.2	c.241G>A	p.Val81Ile	missense_variant	2/14	ENST00000383829.7	NP_001003694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRPF1	ENST00000383829.7	c.241G>A	p.Val81Ile	missense_variant	2/14	1	NM_001003694.2	ENSP00000373340	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual developmental disorder with dysmorphic facies and ptosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Dec 27, 2019

The c.241G>A (p.Val81Ile) variant identified in the BRPF1 gene of this individual substitutes a well conserved Valine for Isoleucine at amino acid 81/1221 (coding exon 2/14). This variant is absent from gnomAD suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Neutral (Provean; score:0.36) and Tolerated (SIFT; score: 0.558) to the function of the canonical transcript. This variant is absent from ClinVar and to our current knowledge has not been reported in affected individuals in the literature. Given the lack of compelling evidence for its pathogenicity, the c.241G>A (p.Val81Ile) variant identified in the BRPF1 gene is reported as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	22
DANN	Benign	0.86
DEOGEN2	Benign	0.021	.;.;.;.;.;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.86	D;D;D;T;T;D
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.053	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N;N;N;.;.;N
MutationTaster	Benign	0.82	N;N;N;N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.44	N;N;N;N;N;N
REVEL	Benign	0.042
Sift	Benign	0.56	T;T;T;T;T;T
Sift4G	Benign	0.68	T;T;T;T;T;T
Polyphen		0.0	B;B;B;.;.;B
Vest4		0.095
MutPred		0.10		Loss of MoRF binding (P = 0.1374);Loss of MoRF binding (P = 0.1374);Loss of MoRF binding (P = 0.1374);Loss of MoRF binding (P = 0.1374);Loss of MoRF binding (P = 0.1374);Loss of MoRF binding (P = 0.1374);
MVP		0.30
MPC		0.67
ClinPred		0.29	T
GERP RS		2.9
Varity_R		0.032
gMVP		0.084

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

LitVar

Other links and lift over

dbSNP: rs2076904769; hg19: chr3-9776065;