chr19-15238785-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 13/21 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.406

Publications

6 publications found

Variant links:

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]

BRD4 Gene-Disease associations (from GenCC):

syndromic intellectual disability
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Cornelia de Lange syndrome 6
Inheritance: AD Classification: STRONG Submitted by: G2P
Cornelia de Lange syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
multiple congenital anomalies/dysmorphic syndrome
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

BRD4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 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 VariationId is 718290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00101 (154/152382) while in subpopulation AMR AF = 0.00882 (135/15314). AF 95% confidence interval is 0.00761. There are 2 homozygotes in GnomAd4. There are 90 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 154 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379291.1. 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
	BRD4	NM_001379291.1	MANE Select	c.3978G>T	p.Glu1326Asp	missense	Exon 19 of 20	NP_001366220.1	O60885-1
	BRD4	NM_058243.3		c.3978G>T	p.Glu1326Asp	missense	Exon 19 of 20	NP_490597.1	O60885-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRD4	ENST00000679869.1	MANE Select	c.3978G>T	p.Glu1326Asp	missense	Exon 19 of 20	ENSP00000506350.1	O60885-1
	BRD4	ENST00000263377.6	TSL:1	c.3978G>T	p.Glu1326Asp	missense	Exon 19 of 20	ENSP00000263377.1	O60885-1

Frequencies

GnomAD3 genomes

AF:

0.00101

AC:

154

AN:

152266

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00359

AC:

831

AN:

231328

AF XY:

0.00288

show subpopulations

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 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.:

Cov.:

AF XY:

0.000709

AC XY:

502

AN XY:

707918

show subpopulations

African (AFR)

AF:

0.0000306

AC:

AN:

32654

American (AMR)

AF:

0.0214

AC:

898

AN:

42058

Ashkenazi Jewish (ASJ)

AF:

0.00135

AC:

AN:

25098

East Asian (EAS)

AF:

0.000615

AC:

AN:

39052

South Asian (SAS)

AF:

0.000451

AC:

AN:

84262

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51880

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4818

European-Non Finnish (NFE)

AF:

0.000118

AC:

129

AN:

1093574

Other (OTH)

AF:

0.000374

AC:

AN:

58772

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

119

178

238

297

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00101

AC:

154

AN:

152382

Hom.:

Cov.:

AF XY:

0.00121

AC XY:

AN XY:

74520

show subpopulations

African (AFR)

AF:

0.0000721

AC:

AN:

41596

American (AMR)

AF:

0.00882

AC:

135

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00154

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68038

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000746

Hom.:

Bravo

AF:

0.00206

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00273

AC:

331

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

BRD4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.098

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0068

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.6

PhyloP100

0.41

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.82

REVEL

Benign

0.15

Sift

Benign

0.078

Sift4G

Benign

0.096

Polyphen

0.99

Vest4

0.36

MutPred

0.17

Gain of MoRF binding (P = 0.0947)

MVP

0.37

MPC

1.1

ClinPred

0.055

GERP RS

-4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.095

gMVP

0.39

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over