21-39247830-CGA-GCT

Variant names:

• chr21-39247830-CGA-GCT
• NM_033656.4:c.2350_2352delTCGinsAGC
• BRWD1 p.785

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP7

The NM_033656.4(BRWD1):​c.2350_2352delTCGinsAGC​(p.785) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. 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)
• Consequence: BRWD1 NM_033656.4 splice_region, synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.484
• Publications: 0 publications found

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

ENSG00000297893 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP7: Synonymous conserved (PhyloP=0.484 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033656.4. 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
	BRWD1	NM_033656.4	MANE Select	c.2350_2352delTCGinsAGC	p.785	splice_region synonymous	N/A	NP_387505.1	Q9NSI6-2
	BRWD1	NM_018963.5		c.2350_2352delTCGinsAGC	p.785	splice_region synonymous	N/A	NP_061836.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRWD1	ENST00000342449.8	TSL:1 MANE Select	c.2350_2352delTCGinsAGC	p.785	splice_region synonymous	N/A	ENSP00000344333.3	Q9NSI6-2
	BRWD1	ENST00000333229.6	TSL:1	c.2350_2352delTCGinsAGC	p.785	splice_region synonymous	N/A	ENSP00000330753.2	Q9NSI6-1
	BRWD1	ENST00000380800.7	TSL:1	c.2350_2352delTCGinsAGC	p.785	splice_region synonymous	N/A	ENSP00000370178.3	Q9NSI6-3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.48

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr21-40619756;