rs34123504

Positions:

• chr11-118901038-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378213.1(BCL9L):​c.2705T>C​(p.Val902Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,577,720 control chromosomes in the GnomAD database, including 391 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (53 hom., cov: 32)
  • Exomes 𝑓: 0.011 (338 hom.)
• Consequence: BCL9L NM_001378213.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.38

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002446711).
• BP6: Variant 11-118901038-A-G is Benign according to our data. Variant chr11-118901038-A-G is described in ClinVar as [Benign]. Clinvar id is 402414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BCL9L	NM_001378213.1	c.2705T>C	p.Val902Ala	missense_variant	8/10	ENST00000683865.1	NP_001365142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCL9L	ENST00000683865.1	c.2705T>C	p.Val902Ala	missense_variant	8/10		NM_001378213.1	ENSP00000507778	P4
BCL9L	ENST00000334801.7	c.2705T>C	p.Val902Ala	missense_variant	6/8	1		ENSP00000335320	P4
BCL9L	ENST00000526143.2	c.2594T>C	p.Val865Ala	missense_variant	6/8	5		ENSP00000482938	A1
BCL9L	ENST00000530293.1	n.41-277T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1929 AN: 152088 Hom.: 53 Cov.: 32

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00609

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.113

Gnomad SAS AF: 0.0165

Gnomad FIN AF: 0.0492

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00760

Gnomad OTH AF: 0.00862

GnomAD3 exomes AF: 0.0199 AC: 4465 AN: 224230 Hom.: 196 AF XY: 0.0198 AC XY: 2375 AN XY: 120040

Gnomad AFR exome AF: 0.00294

Gnomad AMR exome AF: 0.00227

Gnomad ASJ exome AF: 0.00514

Gnomad EAS exome AF: 0.128

Gnomad SAS exome AF: 0.0160

Gnomad FIN exome AF: 0.0434

Gnomad NFE exome AF: 0.00690

Gnomad OTH exome AF: 0.0125

GnomAD4 exome AF: 0.0114 AC: 16292 AN: 1425514 Hom.: 338 Cov.: 35 AF XY: 0.0116 AC XY: 8210 AN XY: 704850

Gnomad4 AFR exome AF: 0.00135

Gnomad4 AMR exome AF: 0.00280

Gnomad4 ASJ exome AF: 0.00350

Gnomad4 EAS exome AF: 0.0908

Gnomad4 SAS exome AF: 0.0163

Gnomad4 FIN exome AF: 0.0416

Gnomad4 NFE exome AF: 0.00744

Gnomad4 OTH exome AF: 0.0147

GnomAD4 genome AF: 0.0127 AC: 1926 AN: 152206 Hom.: 53 Cov.: 32 AF XY: 0.0149 AC XY: 1109 AN XY: 74402

Gnomad4 AFR AF: 0.00221

Gnomad4 AMR AF: 0.00608

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.113

Gnomad4 SAS AF: 0.0166

Gnomad4 FIN AF: 0.0492

Gnomad4 NFE AF: 0.00761

Gnomad4 OTH AF: 0.00853

Alfa AF: 0.0108 Hom.: 55

Bravo AF: 0.00936

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00432 AC: 19

ESP6500EA AF: 0.00722 AC: 62

ExAC AF: 0.0174 AC: 2106

Asia WGS AF: 0.0500 AC: 174 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	19
DANN	Benign	0.84
DEOGEN2	Benign	0.086	T;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.64	T;T
MetaRNN	Benign	0.0024	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;.
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.60	N;.
REVEL	Benign	0.044
Sift	Benign	0.76	T;.
Sift4G	Benign	0.78	T;T
Polyphen		0.040	B;.
Vest4		0.15
MPC		0.25
ClinPred		0.0047	T
GERP RS		4.5
Varity_R		0.036
gMVP		0.26

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: rs34123504; hg19: chr11-118771747;