3-9744393-GC-GCC

Variant names:

• chr3-9744393-G-GC
• rs762904815
• NM_001003694.2:c.2812dupC

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_001003694.2(BRPF1):​c.2812dupC​(p.Gln938ProfsTer15) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,457,924 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: BRPF1 NM_001003694.2 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3
• Conservation: PhyloP100: 7.57
• 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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 3-9744393-G-GC is Pathogenic according to our data. Variant chr3-9744393-G-GC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 521797.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRPF1	NM_001003694.2	c.2812dupC	p.Gln938ProfsTer15	frameshift_variant	Exon 9 of 14	ENST00000383829.7	NP_001003694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRPF1	ENST00000383829.7	c.2812dupC	p.Gln938ProfsTer15	frameshift_variant	Exon 9 of 14	1	NM_001003694.2	ENSP00000373340.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000551 AC: 13 AN: 235928 AF XY: 0.0000155

Gnomad AFR exome AF: 0.000137

Gnomad AMR exome AF: 0.0000304

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000952

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1457924 Hom.: 0 Cov.: 32 AF XY: 0.00000552 AC XY: 4 AN XY: 725222

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33336

American (AMR) AF: 0.0000226 AC: 1 AN: 44228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26032

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.00 AC: 0 AN: 85874

European-Finnish (FIN) AF: 0.000227 AC: 12 AN: 52962

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110056

Other (OTH) AF: 0.0000166 AC: 1 AN: 60102

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Aug 18, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge -

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRPF1: PVS1 -

Inborn genetic diseases Pathogenic:1

May 18, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

May 04, 2022

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Intellectual developmental disorder with dysmorphic facies and ptosis Uncertain:1

Feb 09, 2021

Institute for Human Genetics and Genomic Medicine, Uniklinik RWTH Aachen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The detected change is reported in the dbSNP database (dbSNP150) with the designation rs762904815. In gnomAD it is listed with a frequency of 0.005% (13/235928) (December 18, 2020). The change has already been entered once as pathogenic in ClinVar (RCV000623556.1). The variant leads to a frameshift. Nonsense and frameshift variants in the BRPF1 gene have already been described as disease causing in the literature (Mattioli et al., 2017; Yan et al., 2017). However, these are not subject to a full nonsense-mediated decay. A loss of function of the mutated allele could be shown in various patients, so that haploinsufficiency is assumed to be the underlying disease mechanism. Based on the current state of knowledge, the effect of the change demonstrated here cannot be predicted with certainty, so that, based on the current state of knowledge, the change can be classified as a "variant of uncertain clinical significance" (ACMG criteria). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs762904815; hg19: chr3-9786077; COSMIC: COSV57407917; COSMIC: COSV57407917;