dbSNP rs34752197: BCL9L:p.Met646Leu (chr11-118901807-T-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001378213.1(BCL9L):c.1936A>T(p.Met646Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. 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: 6.9e-7 ( 0 hom. )

Consequence

BCL9L
NM_001378213.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.54

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.113878846).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378213.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BCL9L	NM_001378213.1	MANE Select	c.1936A>T	p.Met646Leu	missense	Exon 8 of 10	NP_001365142.1	Q86UU0-1
BCL9L	NM_182557.4		c.1936A>T	p.Met646Leu	missense	Exon 6 of 8	NP_872363.1	Q86UU0-1
BCL9L	NM_001378214.1		c.1825A>T	p.Met609Leu	missense	Exon 7 of 9	NP_001365143.1	A0A087WZX0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BCL9L	ENST00000683865.1	MANE Select	c.1936A>T	p.Met646Leu	missense	Exon 8 of 10	ENSP00000507778.1	Q86UU0-1
BCL9L	ENST00000334801.7	TSL:1	c.1936A>T	p.Met646Leu	missense	Exon 6 of 8	ENSP00000335320.3	Q86UU0-1
BCL9L	ENST00000913860.1		c.1936A>T	p.Met646Leu	missense	Exon 7 of 9	ENSP00000583919.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458418

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724802

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33416

American (AMR)

AF:

0.00

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:

0.0000116

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: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.039

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.27

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.30

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.70

M_CAP

Benign

0.015

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.5

PhyloP100

5.5

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.53

REVEL

Benign

0.13

Sift

Benign

0.25

Sift4G

Benign

0.70

Polyphen

0.0

Vest4

0.26

MutPred

0.32

Loss of catalytic residue at G647 (P = 0.2344)

MVP

0.53

MPC

0.19

ClinPred

0.19

GERP RS

3.4

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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over