NM_153252.5:c.4786A>G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_153252.5(BRWD3):c.4786A>G(p.Lys1596Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000365 in 1,097,003 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1596Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000036 ( 0 hom. 1 hem. )

Consequence

BRWD3
NM_153252.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 1.61

Publications

3 publications found

Variant links:

Genes affected

BRWD3 (HGNC:17342): (bromodomain and WD repeat domain containing 3) The protein encoded by this gene contains a bromodomain and several WD repeats. It is thought to have a chromatin-modifying function, and may thus play a role in transcription. Mutations in this gene are associated with a spectrum of cognitive disabilities and X-linked macrocephaly. This gene is also associated with translocations in patients with B-cell chronic lymphocytic leukemia. [provided by RefSeq, Jul 2017]

BRWD3 Gene-Disease associations (from GenCC):

intellectual disability, X-linked 93
Inheritance: XL, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
X-linked syndromic intellectual disability
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
infantile spasms
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
self-limited epilepsy with centrotemporal spikes
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

BRWD3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.782

PP5

Variant X-80677232-T-C is Pathogenic according to our data. Variant chrX-80677232-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 10804.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRWD3	NM_153252.5 link	c.4786A>G	p.Lys1596Glu	missense_variant	Exon 41 of 41	ENST00000373275.5	NP_694984.5	Q6RI45-1
BRWD3	NM_001441339.1 link	c.4636A>G	p.Lys1546Glu	missense_variant	Exon 40 of 40		NP_001428268.1
BRWD3	XM_017029384.2 link	c.3574A>G	p.Lys1192Glu	missense_variant	Exon 30 of 30		XP_016884873.1	Q6RI45-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRWD3	ENST00000373275.5 link	c.4786A>G	p.Lys1596Glu	missense_variant	Exon 41 of 41	1	NM_153252.5	ENSP00000362372.4		Q6RI45-1
BRWD3	ENST00000473691.1 link	n.*13A>G		downstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000365

AC:

AN:

1097003

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

362581

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26372

American (AMR)

AF:

0.00

AC:

AN:

35096

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19368

East Asian (EAS)

AF:

0.00

AC:

AN:

30177

South Asian (SAS)

AF:

0.00

AC:

AN:

54084

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40240

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4130

European-Non Finnish (NFE)

AF:

0.00000475

AC:

AN:

841492

Other (OTH)

AF:

0.00

AC:

AN:

46044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Intellectual disability, X-linked 93

Pathogenic:1

Aug 01, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Uncertain

0.099

BayesDel_noAF

Benign

-0.090

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.16

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.65

M_CAP

Benign

0.051

MetaRNN

Pathogenic

0.78

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.3

PhyloP100

1.6

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.53

REVEL

Uncertain

0.37

Sift

Uncertain

0.012

Sift4G

Benign

0.59

Polyphen

0.0

Vest4

0.64

MutPred

0.50

Loss of methylation at K1596 (P = 0.0186);

MVP

0.96

MPC

0.57

ClinPred

0.13

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.19

gMVP

0.21

Mutation Taster

=23/77

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over