chr21-39196921-T-C

Position:

• chr21-39196921-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_033656.4(BRWD1):​c.6148A>G​(p.Thr2050Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000691 in 1,613,902 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0038 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (8 hom.)
• Consequence: BRWD1 NM_033656.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.239

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 -8 ACMG points.

• 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 3.3525 (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=0.0026720762).
• BP6: Variant 21-39196921-T-C is Benign according to our data. Variant chr21-39196921-T-C is described in ClinVar as [Benign]. Clinvar id is 3056259.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRWD1	NM_033656.4	c.6148A>G	p.Thr2050Ala	missense_variant	41/41	ENST00000342449.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRWD1	ENST00000342449.8	c.6148A>G	p.Thr2050Ala	missense_variant	41/41	1	NM_033656.4	A2
BRWD1	ENST00000333229.6	c.6148A>G	p.Thr2050Ala	missense_variant	41/42	1		P2
BRWD1	ENST00000380800.7	c.6148A>G	p.Thr2050Ala	missense_variant	41/42	1		A2
BRWD1	ENST00000446924.5	c.*2472A>G		3_prime_UTR_variant, NMD_transcript_variant	25/26	2

Frequencies

GnomAD3 genomes AF: 0.00382 AC: 582 AN: 152182 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.00287

GnomAD3 exomes AF: 0.000971 AC: 243 AN: 250352 Hom.: 3 AF XY: 0.000695 AC XY: 94 AN XY: 135302

Gnomad AFR exome AF: 0.0145

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000365 AC: 533 AN: 1461602 Hom.: 8 Cov.: 34 AF XY: 0.000316 AC XY: 230 AN XY: 727090

Gnomad4 AFR exome AF: 0.0144

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.000513

GnomAD4 genome AF: 0.00382 AC: 582 AN: 152300 Hom.: 6 Cov.: 32 AF XY: 0.00407 AC XY: 303 AN XY: 74480

Gnomad4 AFR AF: 0.0137

Gnomad4 AMR AF: 0.000327

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: 0.00284

Alfa AF: 0.000462 Hom.: 2

Bravo AF: 0.00435

ESP6500AA AF: 0.0143 AC: 63

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00132 AC: 160

Asia WGS AF: 0.00115 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

BRWD1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 11, 2019

This variant is classified as 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	0.060
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	5.8
DANN	Benign	0.099
DEOGEN2	Benign	0.032	T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0079	N
LIST_S2	Benign	0.33	T;T;T
MetaRNN	Benign	0.0027	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.0	N;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.18	T
PROVEAN	Benign	0.14	N;N;N
REVEL	Benign	0.044
Sift	Benign	0.72	T;T;T
Sift4G	Benign	0.94	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.013
MVP		0.17
MPC		0.062
ClinPred		0.00095	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.032
gMVP		0.024

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: rs73357824; hg19: chr21-40568847;