11-118901807-T-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378213.1(BCL9L):​c.1936A>G​(p.Met646Val) variant causes a missense change. The variant allele was found at a frequency of 0.0115 in 1,610,672 control chromosomes in the GnomAD database, including 398 homozygotes. 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M646L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (53 hom., cov: 32)
  • Exomes 𝑓: 0.011 (345 hom.)
• Consequence: BCL9L NM_001378213.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014236867).
• BP6: Variant 11-118901807-T-C is Benign according to our data. Variant chr11-118901807-T-C is described in ClinVar as Benign. ClinVar VariationId is 402416.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.

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>G	p.Met646Val	missense	Exon 8 of 10	NP_001365142.1	Q86UU0-1
	BCL9L	NM_182557.4		c.1936A>G	p.Met646Val	missense	Exon 6 of 8	NP_872363.1	Q86UU0-1
	BCL9L	NM_001378214.1		c.1825A>G	p.Met609Val	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>G	p.Met646Val	missense	Exon 8 of 10	ENSP00000507778.1	Q86UU0-1
	BCL9L	ENST00000334801.7	TSL:1	c.1936A>G	p.Met646Val	missense	Exon 6 of 8	ENSP00000335320.3	Q86UU0-1
	BCL9L	ENST00000913860.1		c.1936A>G	p.Met646Val	missense	Exon 7 of 9	ENSP00000583919.1

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1928 AN: 152150 Hom.: 53 Cov.: 32

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.113

Gnomad SAS AF: 0.0166

Gnomad FIN AF: 0.0491

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00762

Gnomad OTH AF: 0.00863

GnomAD2 exomes AF: 0.0193 AC: 4826 AN: 250482 AF XY: 0.0190

Gnomad AFR exome AF: 0.00296

Gnomad AMR exome AF: 0.00235

Gnomad ASJ exome AF: 0.00481

Gnomad EAS exome AF: 0.128

Gnomad FIN exome AF: 0.0436

Gnomad NFE exome AF: 0.00692

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.0114 AC: 16656 AN: 1458404 Hom.: 345 Cov.: 36 AF XY: 0.0116 AC XY: 8438 AN XY: 724794

African (AFR) AF: 0.00138 AC: 46 AN: 33416

American (AMR) AF: 0.00278 AC: 124 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00353 AC: 92 AN: 26060

East Asian (EAS) AF: 0.0910 AC: 3600 AN: 39580

South Asian (SAS) AF: 0.0163 AC: 1407 AN: 86146

European-Finnish (FIN) AF: 0.0416 AC: 2216 AN: 53308

Middle Eastern (MID) AF: 0.00313 AC: 18 AN: 5760

European-Non Finnish (NFE) AF: 0.00745 AC: 8261 AN: 1109308

Other (OTH) AF: 0.0148 AC: 892 AN: 60196

GnomAD4 genome AF: 0.0126 AC: 1925 AN: 152268 Hom.: 53 Cov.: 32 AF XY: 0.0149 AC XY: 1111 AN XY: 74456

African (AFR) AF: 0.00221 AC: 92 AN: 41572

American (AMR) AF: 0.00601 AC: 92 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.113 AC: 584 AN: 5172

South Asian (SAS) AF: 0.0166 AC: 80 AN: 4828

European-Finnish (FIN) AF: 0.0491 AC: 521 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00762 AC: 518 AN: 67996

Other (OTH) AF: 0.00854 AC: 18 AN: 2108

Alfa AF: 0.00923 Hom.: 56

Bravo AF: 0.00937

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: 0.0176 AC: 2140

Asia WGS AF: 0.0500 AC: 174 AN: 3478

EpiCase AF: 0.00611

EpiControl AF: 0.00599

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	17
DANN	Benign	0.90
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		5.5
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.14
Sift	Benign	0.051	T
Sift4G	Benign	0.59	T
Polyphen		0.0	B
Vest4		0.40
MPC		0.20
ClinPred		0.012	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.10
gMVP		0.33
Mutation Taster		=97/3	polymorphism (auto)

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; COSMIC: COSV107344545; COSMIC: COSV107344545;