3-9734142-T-G

Position:

• chr3-9734142-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The ENST00000383829.7(BRPF1):​c.2T>G​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRPF1 ENST00000383829.7 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.15

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in ENST00000383829.7 (BRPF1) was described as [Pathogenic] in ClinVar as 489079
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-9734142-T-G is Pathogenic according to our data. Variant chr3-9734142-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1064563.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRPF1	NM_001003694.2	c.2T>G	p.Met1?	start_lost	2/14	ENST00000383829.7	NP_001003694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRPF1	ENST00000383829.7	c.2T>G	p.Met1?	start_lost	2/14	1	NM_001003694.2	ENSP00000373340	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual developmental disorder with dysmorphic facies and ptosis Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

May 01, 2020

The BRPF1 c.2T>G (p.Met1?) variant is rare and is not present in the gnomAD human population database. This variant changes the translation initiator methionine codon. It is not known whether protein translation is completely prevented or if an abnormal protein is produced using an alternate methionine. This variant has not been previously reported in association with autosomal dominant intellectual developmental disorder with dysmorphic facies and ptosis (IDDDFP) . However, another variant affecting the initiator methionine has been reported (ClinVar ID:489079). This variant is considered likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	.;.;.;.;.;T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Uncertain	-0.28	T
MutationTaster	Benign	1.0	D;D;D;D;D
PROVEAN	Benign	-2.0	N;N;N;D;D;N
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0	D;D;D;.;.;D
Vest4		0.94
MutPred		0.97		Gain of MoRF binding (P = 0.0229);Gain of MoRF binding (P = 0.0229);Gain of MoRF binding (P = 0.0229);Gain of MoRF binding (P = 0.0229);Gain of MoRF binding (P = 0.0229);Gain of MoRF binding (P = 0.0229);
MVP		0.83
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.81
gMVP		0.83

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: chr3-9775826;