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

Variant summary

Our verdict is Uncertain significance. Variant got 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 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:

0.00

AC:

AN:

110302

Hom.:

Cov.:

FAILED QC

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

GnomAD3 exomes

AF:

0.0000305

AC:

AN:

131062

Hom.:

AF XY:

0.0000144

AC XY:

AN XY:

69432

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 SAS exome

AF:

0.00

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000724

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000440

Gnomad4 SAS exome

AF:

0.0000833

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000202

Gnomad4 OTH exome

AF:

0.00

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

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000510

Gnomad4 NFE

AF:

0.0000171

Gnomad4 OTH

AF:

0.00

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

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;.;.;.;.

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over