19-15238785-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001379291.1(BRD4):c.3978G>T(p.Glu1326Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00082 in 1,584,550 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0010 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (12 hom.)
• Consequence: BRD4 NM_001379291.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.406

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067904294).
• BP6: Variant 19-15238785-C-A is Benign according to our data. Variant chr19-15238785-C-A is described in ClinVar as [Benign]. Clinvar id is 718290.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0008 (1146/1432168) while in subpopulation AMR AF= 0.0214 (898/42058). AF 95% confidence interval is 0.0202. There are 12 homozygotes in gnomad4_exome. There are 502 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 154 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRD4	NM_001379291.1	c.3978G>T	p.Glu1326Asp	missense_variant	19/20	ENST00000679869.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRD4	ENST00000679869.1	c.3978G>T	p.Glu1326Asp	missense_variant	19/20		NM_001379291.1	P1
BRD4	ENST00000263377.6	c.3978G>T	p.Glu1326Asp	missense_variant	19/20	1		P1

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 154 AN: 152266 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00883

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00359 AC: 831 AN: 231328 Hom.: 11 AF XY: 0.00288 AC XY: 365 AN XY: 126724

Gnomad AFR exome AF: 0.000136

Gnomad AMR exome AF: 0.0240

Gnomad ASJ exome AF: 0.00225

Gnomad EAS exome AF: 0.000451

Gnomad SAS exome AF: 0.000453

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000969

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000800 AC: 1146 AN: 1432168 Hom.: 12 Cov.: 32 AF XY: 0.000709 AC XY: 502 AN XY: 707918

Gnomad4 AFR exome AF: 0.0000306

Gnomad4 AMR exome AF: 0.0214

Gnomad4 ASJ exome AF: 0.00135

Gnomad4 EAS exome AF: 0.000615

Gnomad4 SAS exome AF: 0.000451

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000118

Gnomad4 OTH exome AF: 0.000374

GnomAD4 genome AF: 0.00101 AC: 154 AN: 152382 Hom.: 2 Cov.: 32 AF XY: 0.00121 AC XY: 90 AN XY: 74520

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.00882

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000508 Hom.: 0

Bravo AF: 0.00206

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00273 AC: 331

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	16
Dann	Benign	0.89
DEOGEN2	Benign	0.098	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.53	D
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.15
Sift	Benign	0.078	T
Sift4G	Benign	0.096	T
Polyphen		0.99	D
Vest4		0.36
MutPred		0.17		Gain of MoRF binding (P = 0.0947);
MVP		0.37
MPC		1.1
ClinPred		0.055	T
GERP RS		-4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.095
gMVP		0.39

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: rs201443971; hg19: chr19-15349596;