3-9734336-C-T

Variant names:

• chr3-9734336-C-T
• rs755029735
• NM_001003694.2:c.196C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_001003694.2(BRPF1):​c.196C>T​(p.Arg66Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R66H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRPF1 NM_001003694.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.51
• Publications: 9 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 3-9734336-C-T is Benign according to our data. Variant chr3-9734336-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3064549.Status of the report is criteria_provided_single_submitter, 1 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.196C>T	p.Arg66Cys	missense	Exon 2 of 14	NP_001003694.1	P55201-2
	BRPF1	NM_001437892.1		c.196C>T	p.Arg66Cys	missense	Exon 2 of 13	NP_001424821.1	A0A804HI52
	BRPF1	NM_001438342.1		c.196C>T	p.Arg66Cys	missense	Exon 2 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.196C>T	p.Arg66Cys	missense	Exon 2 of 14	ENSP00000373340.2	P55201-2
	BRPF1	ENST00000424362.7	TSL:1	c.196C>T	p.Arg66Cys	missense	Exon 2 of 14	ENSP00000398863.2	A0A8C8KWW5
	BRPF1	ENST00000919141.1		c.196C>T	p.Arg66Cys	missense	Exon 2 of 13	ENSP00000589200.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 250998 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Intellectual developmental disorder with dysmorphic facies and ptosis (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.094	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	2.0	M
PhyloP100		3.5
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.52
MutPred		0.40		Loss of MoRF binding (P = 0.0502)
MVP		0.58
MPC		2.2
ClinPred		0.99	D
GERP RS		5.7
PromoterAI		0.015	Neutral
Varity_R		0.51
gMVP		0.58
Mutation Taster		=66/34	polymorphism

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: rs755029735; hg19: chr3-9776020; COSMIC: COSV57403970; COSMIC: COSV57403970;