Genetic Variant NM_004326.4:c.337C>T (chr1-147613166-C-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_004326.4(BCL9):c.337C>T(p.Pro113Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,614,144 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 2 hom. )

Consequence

BCL9
NM_004326.4 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 2.93

Publications

4 publications found

Variant links:

Genes affected

BCL9 (HGNC:1008): (BCL9 transcription coactivator) BCL9 is associated with B-cell acute lymphoblastic leukemia. It may be a target of translocation in B-cell malignancies with abnormalities of 1q21. Its function is unknown. The overexpression of BCL9 may be of pathogenic significance in B-cell malignancies. [provided by RefSeq, Jul 2008]

BCL9 Gene-Disease associations (from GenCC):

congenital heart disease
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

BCL9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0059382617).

BP6

Variant 1-147613166-C-T is Benign according to our data. Variant chr1-147613166-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3046009.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAd4 at 188 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004326.4. 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
	BCL9	NM_004326.4	MANE Select	c.337C>T	p.Pro113Ser	missense	Exon 5 of 10	NP_004317.2	O00512

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BCL9	ENST00000234739.8	TSL:1 MANE Select	c.337C>T	p.Pro113Ser	missense	Exon 5 of 10	ENSP00000234739.3	O00512
BCL9	ENST00000683836.1		c.337C>T	p.Pro113Ser	missense	Exon 5 of 10	ENSP00000506908.1	A0A804HI55
BCL9	ENST00000684121.1		c.148+189C>T		intron	N/A	ENSP00000507238.1	A0A804HIV1

Frequencies

GnomAD3 genomes

AF:

0.00124

AC:

188

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00244

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00105

AC:

261

AN:

248672

AF XY:

0.00114

show subpopulations

Gnomad AFR exome

AF:

0.000125

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00197

Gnomad OTH exome

AF:

0.00148

GnomAD4 exome

AF:

0.00134

AC:

1960

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

988

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.000335

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00119

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000174

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000225

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00165

AC:

1832

AN:

1112006

Other (OTH)

AF:

0.000811

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

113

227

340

454

567

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

112

168

224

280

<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:

0.00123

AC:

188

AN:

152258

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41548

American (AMR)

AF:

0.000458

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00244

AC:

166

AN:

68018

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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:

0.00212

Hom.:

Bravo

AF:

0.00109

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.00113

AC:

137

EpiCase

AF:

0.00294

EpiControl

AF:

0.00279

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

BCL9-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.050

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.013

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.78

M_CAP

Benign

0.0019

MetaRNN

Benign

0.0059

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.55

PhyloP100

2.9

PrimateAI

Benign

0.39

PROVEAN

Benign

0.85

REVEL

Benign

0.070

Sift

Benign

0.66

Sift4G

Benign

0.53

Polyphen

0.0010

Vest4

0.12

MVP

0.15

MPC

0.077

ClinPred

0.022

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.061

gMVP

0.057

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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