11-118901807-T-G

Variant names:

• chr11-118901807-T-G
• rs34752197
• NM_001378213.1:c.1936A>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.54
• Publications: 6 publications found

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]

ACMG classification

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.

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

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

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000798 AC: 2 AN: 250482 AF XY: 0.00000738

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: 6 AN: 1458418 Hom.: 0 Cov.: 36 AF XY: 0.00000414 AC XY: 3 AN XY: 724802

African (AFR) AF: 0.00 AC: 0 AN: 33416

American (AMR) AF: 0.000134 AC: 6 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39582

South Asian (SAS) AF: 0.00 AC: 0 AN: 86148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109312

Other (OTH) AF: 0.00 AC: 0 AN: 60198

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 56

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	18
DANN	Benign	0.88
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.5	L
PhyloP100		5.5
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.13
Sift	Benign	0.25	T
Sift4G	Benign	0.70	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	T
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

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

Other links and lift over

dbSNP: rs34752197; hg19: chr11-118772516;