21-39187403-C-T

Position:

• chr21-39187403-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM2 PP2 BP4_Strong BP6_Moderate

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 (★).

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000057 (0 hom.)
• Consequence: BRWD1 ENST00000333229.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, BRWD1
• 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 criteria_provided_single_submitter, 1 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: 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 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;