11-118898510-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001378213.1(BCL9L):c.4405A>C(p.Met1469Leu) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BCL9L NM_001378213.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.79

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2341047).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCL9L	NM_001378213.1	c.4405A>C	p.Met1469Leu	missense_variant	10/10	ENST00000683865.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCL9L	ENST00000683865.1	c.4405A>C	p.Met1469Leu	missense_variant	10/10		NM_001378213.1	P4
BCL9L	ENST00000334801.7	c.4405A>C	p.Met1469Leu	missense_variant	8/8	1		P4
BCL9L	ENST00000526143.2	c.4294A>C	p.Met1432Leu	missense_variant	8/8	5		A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1449214 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 718652

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2022

The c.4405A>C (p.M1469L) alteration is located in exon 8 (coding exon 8) of the BCL9L gene. This alteration results from a A to C substitution at nucleotide position 4405, causing the methionine (M) at amino acid position 1469 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	0.18
BayesDel_addAF	Benign	0.0046	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	19
Dann	Benign	0.92
DEOGEN2	Benign	0.24	T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.098
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	0.89	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.6	N;.
REVEL	Benign	0.28
Sift	Benign	0.084	T;.
Sift4G	Benign	0.33	T;T
Polyphen		0.0030	B;.
Vest4		0.48
MutPred		0.27		Loss of catalytic residue at M1469 (P = 0.0325);.;
MVP		0.70
MPC		0.19
ClinPred		0.51	D
GERP RS		3.7
Varity_R		0.37
gMVP		0.17

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-118769219;