5-138164976-G-T

Variant names:

• chr5-138164976-G-T
• rs11750814
• NM_139199.2:c.1469C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_139199.2(BRD8):​c.1469C>A​(p.Thr490Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T490A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRD8 NM_139199.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.98
• Publications: 38 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32999521).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139199.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRD8	NM_139199.2	MANE Select	c.1469C>A	p.Thr490Lys	missense	Exon 12 of 27	NP_631938.2	Q9H0E9-1
	BRD8	NM_006696.5		c.1688C>A	p.Thr563Lys	missense	Exon 13 of 22	NP_006687.3
	BRD8	NM_001164326.2		c.1478C>A	p.Thr493Lys	missense	Exon 12 of 20	NP_001157798.1	Q9H0E9-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRD8	ENST00000254900.10	TSL:1 MANE Select	c.1469C>A	p.Thr490Lys	missense	Exon 12 of 27	ENSP00000254900.5	Q9H0E9-1
	BRD8	ENST00000230901.9	TSL:1	c.1688C>A	p.Thr563Lys	missense	Exon 13 of 22	ENSP00000230901.5	Q9H0E9-2
	BRD8	ENST00000454473.5	TSL:5	c.1556C>A	p.Thr519Lys	missense	Exon 13 of 21	ENSP00000398067.1	H7C127

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 7136

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.0069	T
Eigen	Benign	-0.037
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		5.0
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.061
Sift	Benign	0.032	D
Sift4G	Benign	0.40	T
Polyphen		0.094	B
Vest4		0.17
MutPred		0.22		Gain of ubiquitination at T490 (P = 0.0014)
MVP		0.46
MPC		0.22
ClinPred		0.28	T
GERP RS		5.5
Varity_R		0.11
gMVP		0.35
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs11750814; hg19: chr5-137500665;