chr21-39187403-C-T

Position:

• chr21-39187403-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM2 PP2 BP4_Strong BP6

The ENST00000333229.6(BRWD1):​c.6586G>A​(p.Asp2196Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000107 in 1,556,690 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000057 (0 hom.)
• Consequence: BRWD1 ENST00000333229.6 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 3.32

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), BRWD1. . Gene score misZ 2.8458 (greater than the threshold 3.09). Trascript score misZ 3.2872 (greater than threshold 3.09). GenCC has associacion of gene with ciliary dyskinesia, primary, 51, agammaglobulinemia, primary ciliary dyskinesia.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0061485767).
• BP6: Variant 21-39187403-C-T is Benign according to our data. Variant chr21-39187403-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3052779.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRWD1	NM_033656.4	c.*8856G>A		3_prime_UTR_variant	41/41	ENST00000342449.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRWD1	ENST00000333229.6	c.6586G>A	p.Asp2196Asn	missense_variant	42/42	1		P2
BRWD1	ENST00000342449.8	c.*8856G>A		3_prime_UTR_variant	41/41	1	NM_033656.4	A2
BRWD1	ENST00000446924.5	c.*2910G>A		3_prime_UTR_variant, NMD_transcript_variant	26/26	2

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 84 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000222 AC: 46 AN: 207312 Hom.: 0 AF XY: 0.000159 AC XY: 18 AN XY: 113262

Gnomad AFR exome AF: 0.00277

Gnomad AMR exome AF: 0.000135

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000868

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000570 AC: 80 AN: 1404426 Hom.: 0 Cov.: 31 AF XY: 0.0000446 AC XY: 31 AN XY: 694634

Gnomad4 AFR exome AF: 0.00212

Gnomad4 AMR exome AF: 0.000251

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000129

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000865

GnomAD4 genome AF: 0.000565 AC: 86 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.000524 AC XY: 39 AN XY: 74446

Gnomad4 AFR AF: 0.00193

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000311 Hom.: 0

Bravo AF: 0.000669

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000214 AC: 26

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

BRWD1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 02, 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	0.093
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Benign	0.058	T
Eigen	Benign	-0.044
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	0.70	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.082
Sift	Uncertain	0.024	D
Sift4G	Benign	0.11	T
Polyphen		0.0050	B
Vest4		0.14
MVP		0.50
MPC		0.37
ClinPred		0.059	T
GERP RS		4.6
Varity_R		0.12
gMVP		0.026

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs146778195; hg19: chr21-40559329;