11-118901807-T-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001378213.1(BCL9L):c.1936A>C(p.Met646Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,458,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M646V) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

BCL9L
NM_001378213.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.54

Publications

6 publications found

Variant links:

Genes affected

BCL9L (HGNC:23688): (BCL9 like) Enables beta-catenin binding activity. Involved in several processes, including negative regulation of transforming growth factor beta receptor signaling pathway; positive regulation of epithelial to mesenchymal transition; and positive regulation of transcription by RNA polymerase II. Located in nucleolus and nucleoplasm. Part of beta-catenin-TCF complex. [provided by Alliance of Genome Resources, Apr 2022]

BCL9L links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.110309064).

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCL9L	NM_001378213.1 link	c.1936A>C	p.Met646Leu	missense_variant	Exon 8 of 10	ENST00000683865.1	NP_001365142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BCL9L	ENST00000683865.1 link	c.1936A>C	p.Met646Leu	missense_variant	Exon 8 of 10		NM_001378213.1	ENSP00000507778.1	Q86UU0-1
BCL9L	ENST00000334801.7 link	c.1936A>C	p.Met646Leu	missense_variant	Exon 6 of 8	1		ENSP00000335320.3	Q86UU0-1
BCL9L	ENST00000526143.2 link	c.1825A>C	p.Met609Leu	missense_variant	Exon 6 of 8	5		ENSP00000482938.1	A0A087WZX0
BCL9L	ENST00000530293.1 link	n.41-1046A>C		intron_variant	Intron 1 of 2	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000798

AC:

AN:

250482

AF XY:

0.00000738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1458418

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

724802

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33416

American (AMR)

AF:

0.000134

AC:

AN:

44630

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26060

East Asian (EAS)

AF:

0.00

AC:

AN:

39582

South Asian (SAS)

AF:

0.00

AC:

AN:

86148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53312

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109312

Other (OTH)

AF:

0.00

AC:

AN:

60198

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 17, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1936A>C (p.M646L) alteration is located in exon 6 (coding exon 6) of the BCL9L gene. This alteration results from a A to C substitution at nucleotide position 1936, causing the methionine (M) at amino acid position 646 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.27

T;.

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.30

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.70

T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.5

L;.

PhyloP100

5.5

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.53

N;.

REVEL

Benign

0.13

Sift

Benign

0.25

T;.

Sift4G

Benign

0.70

T;T

Polyphen

0.0

B;.

Vest4

0.26

MutPred

0.32

Loss of catalytic residue at G647 (P = 0.2344);.;

MVP

0.53

MPC

0.19

ClinPred

0.072

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.057

gMVP

0.21

Mutation Taster

=96/4

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over