11-118902116-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001378213.1(BCL9L):c.1627A>C(p.Ser543Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. S543G) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BCL9L NM_001378213.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.92

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04851532).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCL9L	NM_001378213.1	c.1627A>C	p.Ser543Arg	missense_variant	8/10	ENST00000683865.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCL9L	ENST00000683865.1	c.1627A>C	p.Ser543Arg	missense_variant	8/10		NM_001378213.1	P4
BCL9L	ENST00000334801.7	c.1627A>C	p.Ser543Arg	missense_variant	6/8	1		P4
BCL9L	ENST00000526143.2	c.1516A>C	p.Ser506Arg	missense_variant	6/8	5		A1
BCL9L	ENST00000530293.1	n.41-1355A>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	18
Dann	Benign	0.83
DEOGEN2	Benign	0.097	T;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.52	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.049	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.77	N;.
REVEL	Benign	0.11
Sift	Benign	0.41	T;.
Sift4G	Benign	0.46	T;T
Polyphen		0.0020	B;.
Vest4		0.19
MutPred		0.22		Loss of phosphorylation at S543 (P = 0.021);.;
MVP		0.10
MPC		0.23
ClinPred		0.092	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.040
gMVP		0.18

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

LitVar

Other links and lift over

dbSNP: rs78780803; hg19: chr11-118772825;