Genetic Variant BRWD1:p.Ser784Ser (chr21-39247830-C-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_033656.4(BRWD1):c.2352G>T(p.Ser784Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,439,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S784S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

BRWD1
NM_033656.4 splice_region, synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.744

Publications

0 publications found

Variant links:

Genes affected

BRWD1 (HGNC:12760): (bromodomain and WD repeat domain containing 1) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD) residues which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes including cell cycle progression, signal transduction, apoptosis, and gene regulation. This protein contains 2 bromodomains and multiple WD repeats. This gene is located within the Down syndrome region-2 on chromosome 21. Alternative splicing of this gene generates multiple transcript variants encoding distinct isoforms. In mouse, this gene encodes a nuclear protein that has a polyglutamine-containing region that functions as a transcriptional activation domain which may regulate chromatin remodelling and associates with a component of the SWI/SNF chromatin remodelling complex.[provided by RefSeq, Jun 2011]

BRWD1 Gene-Disease associations (from GenCC):

agammaglobulinemia
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
ciliary dyskinesia, primary, 51
Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
primary ciliary dyskinesia
Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

BRWD1 links:

ENSG00000297893 (HGNC:):

ENSG00000297893 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP7

Synonymous conserved (PhyloP=-0.744 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRWD1	NM_033656.4 link	c.2352G>T	p.Ser784Ser	splice_region_variant, synonymous_variant	Exon 21 of 41	ENST00000342449.8	NP_387505.1	Q9NSI6-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRWD1	ENST00000342449.8 link	c.2352G>T	p.Ser784Ser	splice_region_variant, synonymous_variant	Exon 21 of 41	1	NM_033656.4	ENSP00000344333.3		Q9NSI6-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.95e-7

AC:

AN:

1439608

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

715404

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

32500

American (AMR)

AF:

0.00

AC:

AN:

40424

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25306

East Asian (EAS)

AF:

0.00

AC:

AN:

38904

South Asian (SAS)

AF:

0.00

AC:

AN:

81694

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53058

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5672

European-Non Finnish (NFE)

AF:

9.07e-7

AC:

AN:

1102718

Other (OTH)

AF:

0.00

AC:

AN:

59332

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.77

(source)

DANN

Benign

0.63

PhyloP100

-0.74

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over