NM_014038.3:c.488C>T

Variant names:

• chr7-16685987-C-T
• rs374366357
• NM_014038.3:c.488C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_014038.3(BZW2):​c.488C>T​(p.Thr163Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000393 in 1,603,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: BZW2 NM_014038.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.12
• Publications: 1 publications found

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]

ENSG00000235837 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07057035).
• BS2: High AC in GnomAd4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BZW2	NM_014038.3	c.488C>T	p.Thr163Ile	missense_variant	Exon 6 of 12	ENST00000258761.8	NP_054757.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BZW2	ENST00000258761.8	c.488C>T	p.Thr163Ile	missense_variant	Exon 6 of 12	1	NM_014038.3	ENSP00000258761.3

Frequencies

GnomAD3 genomes AF: 0.000179 AC: 27 AN: 151060 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000585

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000662

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000298 AC: 7 AN: 234828 AF XY: 0.0000317

Gnomad AFR exome AF: 0.000346

Gnomad AMR exome AF: 0.0000302

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000248 AC: 36 AN: 1452076 Hom.: 0 Cov.: 36 AF XY: 0.0000194 AC XY: 14 AN XY: 720972

African (AFR) AF: 0.000629 AC: 21 AN: 33398

American (AMR) AF: 0.0000459 AC: 2 AN: 43540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25742

East Asian (EAS) AF: 0.00 AC: 0 AN: 39506

South Asian (SAS) AF: 0.0000239 AC: 2 AN: 83740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52626

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5760

European-Non Finnish (NFE) AF: 0.00000632 AC: 7 AN: 1107714

Other (OTH) AF: 0.0000333 AC: 2 AN: 60050

GnomAD4 genome AF: 0.000179 AC: 27 AN: 151172 Hom.: 0 Cov.: 31 AF XY: 0.000163 AC XY: 12 AN XY: 73734

African (AFR) AF: 0.000583 AC: 24 AN: 41144

American (AMR) AF: 0.0000661 AC: 1 AN: 15130

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5104

South Asian (SAS) AF: 0.00 AC: 0 AN: 4786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67926

Other (OTH) AF: 0.00 AC: 0 AN: 2098

Alfa AF: 0.0000330 Hom.: 0

Bravo AF: 0.000223

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.488C>T (p.T163I) 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 488, causing the threonine (T) at amino acid position 163 to be replaced by an isoleucine (I). 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	Benign	0.19
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0096	T;T;T;T;T;.;T
Eigen	Benign	-0.064
Eigen_PC	Benign	-0.069
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.85	T;.;T;T;D;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.071	T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.92	.;L;L;.;.;.;.
PhyloP100		1.1
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.91	N;N;N;N;N;.;N
REVEL	Benign	0.11
Sift	Benign	0.22	T;T;T;T;T;.;T
Sift4G	Benign	0.24	T;T;T;T;T;T;T
Polyphen		0.99	D;D;D;.;.;.;.
Vest4		0.55, 0.55, 0.53, 0.53
MVP		0.41
MPC		0.58
ClinPred		0.13	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.073
gMVP		0.49
Mutation Taster		=77/23	polymorphism

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: rs374366357; hg19: chr7-16725612;