Genetic Variant BZW2:p.Leu137Phe (chr7-16685908-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_014038.3(BZW2):c.409C>T(p.Leu137Phe) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L137P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 26)

Exomes 𝑓: 0.000023 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

BZW2
NM_014038.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.86

Publications

1 publications found

Variant links:

Genes affected

BZW2 (HGNC:18808): (basic leucine zipper and W2 domains 2) Enables cadherin binding activity. Predicted to be involved in cell differentiation and nervous system development. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

BZW2 links:

ENSG00000235837 (HGNC:):

ENSG00000235837 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.79

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BZW2	NM_014038.3 link	c.409C>T	p.Leu137Phe	missense_variant	Exon 6 of 12	ENST00000258761.8	NP_054757.1	Q9Y6E2-1A0A024RA42

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BZW2	ENST00000258761.8 link	c.409C>T	p.Leu137Phe	missense_variant	Exon 6 of 12	1	NM_014038.3	ENSP00000258761.3		Q9Y6E2-1

Frequencies

GnomAD3 genomes

AF:

0.0000272

AC:

AN:

110302

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000510

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000171

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000305

AC:

AN:

131062

AF XY:

0.0000144

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000488

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000196

Gnomad OTH exome

AF:

0.000280

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000232

AC:

AN:

1077108

Hom.:

Cov.:

AF XY:

0.0000361

AC XY:

AN XY:

526882

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

22846

American (AMR)

AF:

0.0000724

AC:

AN:

27626

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18176

East Asian (EAS)

AF:

0.0000440

AC:

AN:

22732

South Asian (SAS)

AF:

0.0000833

AC:

AN:

60040

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37022

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3776

European-Non Finnish (NFE)

AF:

0.0000202

AC:

AN:

842218

Other (OTH)

AF:

0.00

AC:

AN:

42672

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.229

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000272

AC:

AN:

110302

Hom.:

Cov.:

AF XY:

0.0000592

AC XY:

AN XY:

50694

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

27658

American (AMR)

AF:

0.00

AC:

AN:

8084

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3070

East Asian (EAS)

AF:

0.00

AC:

AN:

3362

South Asian (SAS)

AF:

0.00

AC:

AN:

3220

European-Finnish (FIN)

AF:

0.000510

AC:

AN:

3920

Middle Eastern (MID)

AF:

0.00

AC:

AN:

108

European-Non Finnish (NFE)

AF:

0.0000171

AC:

AN:

58614

Other (OTH)

AF:

0.00

AC:

AN:

1446

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 07, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.409C>T (p.L137F) alteration is located in exon 6 (coding exon 5) of the BZW2 gene. This alteration results from a C to T substitution at nucleotide position 409, causing the leucine (L) at amino acid position 137 to be replaced by a phenylalanine (F). 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

Uncertain

0.51

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.26

T;T;T;T;T;T;T

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

1.0

D;.;D;D;D;D;D

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.79

D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.054

MutationAssessor

Uncertain

2.7

.;M;M;.;.;.;.

PhyloP100

7.9

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.6

D;D;D;D;D;D;D

REVEL

Uncertain

0.43

Sift

Uncertain

0.0030

D;D;D;D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D;D;D;D

Polyphen

0.99

D;D;D;.;.;.;.

Vest4

0.79, 0.79, 0.87

MutPred

0.68

Gain of methylation at K141 (P = 0.0698);Gain of methylation at K141 (P = 0.0698);Gain of methylation at K141 (P = 0.0698);.;Gain of methylation at K141 (P = 0.0698);Gain of methylation at K141 (P = 0.0698);Gain of methylation at K141 (P = 0.0698);

MVP

0.51

MPC

1.1

ClinPred

0.70

GERP RS

5.0

Varity_R

0.62

gMVP

0.77

Mutation Taster

=16/84

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

7-16685908-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over