NM_001003694.2:c.2982C>G

Variant names:

• chr3-9745069-C-G
• rs1057519514
• NM_001003694.2:c.2982C>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001003694.2(BRPF1):​c.2982C>G​(p.Tyr994*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BRPF1 NM_001003694.2 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.54
• Publications: 1 publications found

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]

BRPF1 Gene-Disease associations (from GenCC):

• intellectual developmental disorder with dysmorphic facies and ptosis

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics
• syndromic complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-9745069-C-G is Pathogenic according to our data. Variant chr3-9745069-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 375490.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001003694.2. 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
	BRPF1	NM_001003694.2	MANE Select	c.2982C>G	p.Tyr994*	stop_gained	Exon 10 of 14	NP_001003694.1	P55201-2
	BRPF1	NM_001437892.1		c.2964C>G	p.Tyr988*	stop_gained	Exon 10 of 13	NP_001424821.1	A0A804HI52
	BRPF1	NM_001438342.1		c.2961C>G	p.Tyr987*	stop_gained	Exon 10 of 13	NP_001425271.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRPF1	ENST00000383829.7	TSL:1 MANE Select	c.2982C>G	p.Tyr994*	stop_gained	Exon 10 of 14	ENSP00000373340.2	P55201-2
	BRPF1	ENST00000424362.7	TSL:1	c.2979C>G	p.Tyr993*	stop_gained	Exon 10 of 14	ENSP00000398863.2	A0A8C8KWW5
	BRPF1	ENST00000919141.1		c.2982C>G	p.Tyr994*	stop_gained	Exon 10 of 13	ENSP00000589200.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Intellectual developmental disorder with dysmorphic facies and ptosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.91	D
PhyloP100		1.5
Vest4		0.80
GERP RS		-0.43
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1057519514; hg19: chr3-9786753;