19-15238816-T-A

Variant names:

• chr19-15238816-T-A
• rs2047213875
• NM_001379291.1:c.3947A>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001379291.1(BRD4):​c.3947A>T​(p.Gln1316Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,451,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BRD4 NM_001379291.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.13

Genes affected

BRD4 (HGNC:13575): (bromodomain containing 4) The protein encoded by this gene is homologous to the murine protein MCAP, which associates with chromosomes during mitosis, and to the human RING3 protein, a serine/threonine kinase. Each of these proteins contains two bromodomains, a conserved sequence motif which may be involved in chromatin targeting. This gene has been implicated as the chromosome 19 target of translocation t(15;19)(q13;p13.1), which defines an upper respiratory tract carcinoma in young people. Two alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17883533).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRD4	NM_001379291.1	c.3947A>T	p.Gln1316Leu	missense_variant	Exon 19 of 20	ENST00000679869.1	NP_001366220.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRD4	ENST00000679869.1	c.3947A>T	p.Gln1316Leu	missense_variant	Exon 19 of 20		NM_001379291.1	ENSP00000506350.1
BRD4	ENST00000263377.6	c.3947A>T	p.Gln1316Leu	missense_variant	Exon 19 of 20	1		ENSP00000263377.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451170 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 720312

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.04e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 20, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. This variant has not been reported in the literature in individuals affected with BRD4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1316 of the BRD4 protein (p.Gln1316Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Benign	0.93
DEOGEN2	Benign	0.11	T
Eigen	Benign	0.081
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.2	L
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.11
Sift	Benign	0.17	T
Sift4G	Benign	0.094	T
Polyphen		0.18	B
Vest4		0.46
MutPred		0.15		Gain of helix (P = 0.062);
MVP		0.50
MPC		0.97
ClinPred		0.56	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.41

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: rs2047213875; hg19: chr19-15349627;