11-118898594-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001378213.1(BCL9L):c.4321G>A(p.Val1441Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 1,611,814 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0051 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (4 hom.)
• Consequence: BCL9L NM_001378213.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.30

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035871565).
• BP6: Variant 11-118898594-C-T is Benign according to our data. Variant chr11-118898594-C-T is described in ClinVar as [Benign]. Clinvar id is 781048.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00513 (782/152316) while in subpopulation AFR AF= 0.0179 (743/41580). AF 95% confidence interval is 0.0168. There are 6 homozygotes in gnomad4. There are 372 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 781 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCL9L	NM_001378213.1	c.4321G>A	p.Val1441Met	missense_variant	10/10	ENST00000683865.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCL9L	ENST00000683865.1	c.4321G>A	p.Val1441Met	missense_variant	10/10		NM_001378213.1	P4
BCL9L	ENST00000334801.7	c.4321G>A	p.Val1441Met	missense_variant	8/8	1		P4
BCL9L	ENST00000526143.2	c.4210G>A	p.Val1404Met	missense_variant	8/8	5		A1

Frequencies

GnomAD3 genomes AF: 0.00513 AC: 781 AN: 152198 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00128 AC: 313 AN: 243620 Hom.: 4 AF XY: 0.00111 AC XY: 148 AN XY: 133232

Gnomad AFR exome AF: 0.0169

Gnomad AMR exome AF: 0.00117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000549

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000120

Gnomad OTH exome AF: 0.000503

GnomAD4 exome AF: 0.000626 AC: 914 AN: 1459498 Hom.: 4 Cov.: 35 AF XY: 0.000561 AC XY: 407 AN XY: 725992

Gnomad4 AFR exome AF: 0.0176

Gnomad4 AMR exome AF: 0.00128

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000173

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.00513 AC: 782 AN: 152316 Hom.: 6 Cov.: 32 AF XY: 0.00499 AC XY: 372 AN XY: 74476

Gnomad4 AFR AF: 0.0179

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000808 Hom.: 1

Bravo AF: 0.00566

ESP6500AA AF: 0.0189 AC: 83

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.00156 AC: 189

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Mar 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.10	T;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.76	T;T
MetaRNN	Benign	0.0036	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.81	N;.
MutationTaster	Benign	0.98	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.49	N;.
REVEL	Benign	0.036
Sift	Benign	0.13	T;.
Sift4G	Benign	0.31	T;T
Polyphen		0.063	B;.
Vest4		0.20
MVP		0.32
MPC		0.44
ClinPred		0.024	T
GERP RS		3.3
Varity_R		0.081
gMVP		0.098

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: rs79654456; hg19: chr11-118769303; COSMIC: COSV99418768; COSMIC: COSV99418768;