21-39196550-A-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_033656.4(BRWD1):c.6519T>C(p.Asn2173=) 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 (★).

• 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 criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.129

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]

ACMG classification

Verdict is Benign. Variant got -11 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 id is 3033349.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.129 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRWD1	NM_033656.4	c.6519T>C	p.Asn2173=	synonymous_variant	41/41	ENST00000342449.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRWD1	ENST00000342449.8	c.6519T>C	p.Asn2173=	synonymous_variant	41/41	1	NM_033656.4	A2
BRWD1	ENST00000333229.6	c.6519T>C	p.Asn2173=	synonymous_variant	41/42	1		P2
BRWD1	ENST00000380800.7	c.6519T>C	p.Asn2173=	synonymous_variant	41/42	1		A2
BRWD1	ENST00000446924.5	c.*2843T>C		3_prime_UTR_variant, NMD_transcript_variant	25/26	2

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

GnomAD3 exomes AF: 0.00305 AC: 763 AN: 250356 Hom.: 0 AF XY: 0.00274 AC XY: 371 AN XY: 135296

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 SAS exome AF: 0.000393

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

Gnomad4 AFR exome AF: 0.000867

Gnomad4 AMR exome AF: 0.00284

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.00472

Gnomad4 NFE exome AF: 0.00524

Gnomad4 OTH exome AF: 0.00363

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

Gnomad4 AFR AF: 0.000699

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00406

Gnomad4 NFE AF: 0.00502

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00386 Hom.: 0

Bravo AF: 0.00255

EpiCase AF: 0.00523

EpiControl AF: 0.00433

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

BRWD1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 28, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	1.3
Dann	Benign	0.62

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

LitVar

Other links and lift over

dbSNP: rs141324249; hg19: chr21-40568476; COSMIC: COSV100313252; COSMIC: COSV100313252;