21-39197176-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Strong BP6_Moderate

The NM_033656.4(BRWD1):c.5893C>T(p.Leu1965Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00298 in 1,614,114 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (18 hom.)
• Consequence: BRWD1 NM_033656.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.416

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 Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, BRWD1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0040858984).
• BP6: Variant 21-39197176-G-A is Benign according to our data. Variant chr21-39197176-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3039911.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRWD1	NM_033656.4	c.5893C>T	p.Leu1965Phe	missense_variant	41/41	ENST00000342449.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRWD1	ENST00000342449.8	c.5893C>T	p.Leu1965Phe	missense_variant	41/41	1	NM_033656.4	A2
BRWD1	ENST00000333229.6	c.5893C>T	p.Leu1965Phe	missense_variant	41/42	1		P2
BRWD1	ENST00000380800.7	c.5893C>T	p.Leu1965Phe	missense_variant	41/42	1		A2
BRWD1	ENST00000446924.5	c.*2217C>T		3_prime_UTR_variant, NMD_transcript_variant	25/26	2

Frequencies

GnomAD3 genomes AF: 0.00212 AC: 323 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00313

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00200 AC: 502 AN: 250874 Hom.: 1 AF XY: 0.00181 AC XY: 245 AN XY: 135584

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00281

Gnomad ASJ exome AF: 0.00636

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00261

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00307 AC: 4481 AN: 1461808 Hom.: 18 Cov.: 33 AF XY: 0.00297 AC XY: 2162 AN XY: 727196

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00291

Gnomad4 ASJ exome AF: 0.00651

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000301

Gnomad4 FIN exome AF: 0.000711

Gnomad4 NFE exome AF: 0.00351

Gnomad4 OTH exome AF: 0.00326

GnomAD4 genome AF: 0.00211 AC: 322 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.00211 AC XY: 157 AN XY: 74480

Gnomad4 AFR AF: 0.000625

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.00312

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00303 Hom.: 1

Bravo AF: 0.00245

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00169 AC: 205

EpiCase AF: 0.00294

EpiControl AF: 0.00249

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

Apr 01, 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
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	0.88
Dann	Benign	0.72
DEOGEN2	Benign	0.068	T;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.65	T;T;T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.0041	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;M;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.72	N;N;N
REVEL	Benign	0.080
Sift	Benign	0.032	D;D;T
Sift4G	Benign	0.52	T;T;T
Polyphen		0.53	P;P;.
Vest4		0.029
MVP		0.34
MPC		0.12
ClinPred		0.010	T
GERP RS		0.85
Varity_R		0.11
gMVP		0.027

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: rs61742658; hg19: chr21-40569102; COSMIC: COSV100314418; COSMIC: COSV100314418;