rs11750814

Positions:

• chr5-138164976-G-A
• chr5-138164976-G-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2 BP4_Strong BA1

The NM_139199.2(BRD8):​c.1469C>T​(p.Thr490Met) variant causes a missense change. The variant allele was found at a frequency of 0.169 in 1,613,960 control chromosomes in the GnomAD database, including 24,967 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.13 (1641 hom., cov: 32)
  • Exomes 𝑓: 0.17 (23326 hom.)
• Consequence: BRD8 NM_139199.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.98

Genes affected

BRD8 (HGNC:19874): (bromodomain containing 8) The protein encoded by this gene interacts with thyroid hormone receptor in a ligand-dependent manner and enhances thyroid hormone-dependent activation from thyroid response elements. This protein contains a bromodomain and is thought to be a nuclear receptor coactivator. Multiple alternatively spliced transcript variants that encode distinct isoforms have been identified. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PP2: Missense variant where missense usually causes diseases, BRD8
• BP4: Computational evidence support a benign effect (MetaRNN=0.0015330613).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.207 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRD8	NM_139199.2	c.1469C>T	p.Thr490Met	missense_variant	12/27	ENST00000254900.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRD8	ENST00000254900.10	c.1469C>T	p.Thr490Met	missense_variant	12/27	1	NM_139199.2	P1

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20362 AN: 151960 Hom.: 1643 Cov.: 32

Gnomad AFR AF: 0.0726

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.0913

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.0119

Gnomad SAS AF: 0.218

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.122

GnomAD3 exomes AF: 0.148 AC: 37120 AN: 251362 Hom.: 3223 AF XY: 0.154 AC XY: 20917 AN XY: 135842

Gnomad AFR exome AF: 0.0733

Gnomad AMR exome AF: 0.0852

Gnomad ASJ exome AF: 0.101

Gnomad EAS exome AF: 0.0113

Gnomad SAS exome AF: 0.214

Gnomad FIN exome AF: 0.182

Gnomad NFE exome AF: 0.179

Gnomad OTH exome AF: 0.143

GnomAD4 exome AF: 0.172 AC: 252118 AN: 1461882 Hom.: 23326 Cov.: 33 AF XY: 0.174 AC XY: 126464 AN XY: 727244

Gnomad4 AFR exome AF: 0.0686

Gnomad4 AMR exome AF: 0.0873

Gnomad4 ASJ exome AF: 0.105

Gnomad4 EAS exome AF: 0.0107

Gnomad4 SAS exome AF: 0.216

Gnomad4 FIN exome AF: 0.183

Gnomad4 NFE exome AF: 0.184

Gnomad4 OTH exome AF: 0.155

GnomAD4 genome AF: 0.134 AC: 20357 AN: 152078 Hom.: 1641 Cov.: 32 AF XY: 0.133 AC XY: 9916 AN XY: 74328

Gnomad4 AFR AF: 0.0725

Gnomad4 AMR AF: 0.0911

Gnomad4 ASJ AF: 0.109

Gnomad4 EAS AF: 0.0122

Gnomad4 SAS AF: 0.218

Gnomad4 FIN AF: 0.172

Gnomad4 NFE AF: 0.180

Gnomad4 OTH AF: 0.120

Alfa AF: 0.161 Hom.: 5343

Bravo AF: 0.122

TwinsUK AF: 0.184 AC: 683

ALSPAC AF: 0.181 AC: 699

ESP6500AA AF: 0.0824 AC: 363

ESP6500EA AF: 0.174 AC: 1496

ExAC AF: 0.152 AC: 18453

Asia WGS AF: 0.130 AC: 453 AN: 3478

EpiCase AF: 0.164

EpiControl AF: 0.164

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	T;.;T;.;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.76	T;T;T;T;T;T
MetaRNN	Benign	0.0015	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.;.;.;.;.
MutationTaster	Benign	0.0086	P;P;P;P;P
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.2	N;N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.037	D;D;D;D;D;D
Sift4G	Uncertain	0.046	D;D;T;T;D;T
Polyphen		0.99	D;.;.;D;.;D
Vest4		0.11
MPC		0.41
ClinPred		0.028	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.052
gMVP		0.30

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: rs11750814; hg19: chr5-137500665; COSMIC: COSV50153597; COSMIC: COSV50153597;