rs141324249

Variant names:

• chr21-39196550-A-G
• rs141324249
• NM_033656.4:c.6519T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_033656.4(BRWD1):​c.6519T>C​(p.Asn2173Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0043 in 1,613,584 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (18 hom.)
• Consequence: BRWD1 NM_033656.4 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.129
• Publications: 1 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000297893 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 21-39196550-A-G is Benign according to our data. Variant chr21-39196550-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3033349.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.129 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

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.6519T>C	p.Asn2173Asn	synonymous	Exon 41 of 41	NP_387505.1	Q9NSI6-2
	BRWD1	NM_018963.5		c.6519T>C	p.Asn2173Asn	synonymous	Exon 41 of 42	NP_061836.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRWD1	ENST00000342449.8	TSL:1 MANE Select	c.6519T>C	p.Asn2173Asn	synonymous	Exon 41 of 41	ENSP00000344333.3	Q9NSI6-2
	BRWD1	ENST00000333229.6	TSL:1	c.6519T>C	p.Asn2173Asn	synonymous	Exon 41 of 42	ENSP00000330753.2	Q9NSI6-1
	BRWD1	ENST00000380800.7	TSL:1	c.6519T>C	p.Asn2173Asn	synonymous	Exon 41 of 42	ENSP00000370178.3	Q9NSI6-3

Frequencies

GnomAD3 genomes AF: 0.00303 AC: 461 AN: 151982 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000701

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00276

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00406

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00502

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00305 AC: 763 AN: 250356 AF XY: 0.00274

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00261

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00496

Gnomad NFE exome AF: 0.00464

Gnomad OTH exome AF: 0.00230

GnomAD4 exome AF: 0.00443 AC: 6478 AN: 1461486 Hom.: 18 Cov.: 33 AF XY: 0.00424 AC XY: 3082 AN XY: 727028

African (AFR) AF: 0.000867 AC: 29 AN: 33450

American (AMR) AF: 0.00284 AC: 127 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86212

European-Finnish (FIN) AF: 0.00472 AC: 252 AN: 53356

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00524 AC: 5823 AN: 1111836

Other (OTH) AF: 0.00363 AC: 219 AN: 60376

GnomAD4 genome AF: 0.00303 AC: 461 AN: 152098 Hom.: 2 Cov.: 32 AF XY: 0.00285 AC XY: 212 AN XY: 74362

African (AFR) AF: 0.000699 AC: 29 AN: 41514

American (AMR) AF: 0.00275 AC: 42 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00406 AC: 43 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00502 AC: 341 AN: 67938

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00389 Hom.: 0

Bravo AF: 0.00255

EpiCase AF: 0.00523

EpiControl AF: 0.00433

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	BRWD1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.3
DANN	Benign	0.62
PhyloP100		-0.13
Mutation Taster		=100/0	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: rs141324249; hg19: chr21-40568476; COSMIC: COSV100313252; COSMIC: COSV100313252;