11-25078615-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001009909.4(LUZP2):c.998C>T(p.Thr333Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,459,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: LUZP2 NM_001009909.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.252

Genes affected

LUZP2 (HGNC:23206): (leucine zipper protein 2) This gene encodes a leucine zipper protein. This protein is deleted in some patients with Wilms tumor-Aniridia-Genitourinary anomalies-mental Retardation (WAGR) syndrome. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.046881378).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LUZP2	NM_001009909.4	c.998C>T	p.Thr333Ile	missense_variant	12/12	ENST00000336930.11
LUZP2	NM_001252010.2	c.872C>T	p.Thr291Ile	missense_variant	10/10
LUZP2	NM_001252008.2	c.740C>T	p.Thr247Ile	missense_variant	12/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LUZP2	ENST00000336930.11	c.998C>T	p.Thr333Ile	missense_variant	12/12	1	NM_001009909.4	P1
LUZP2	ENST00000533227.5	c.740C>T	p.Thr247Ile	missense_variant	12/12	1
LUZP2	ENST00000620308.1	c.740C>T	p.Thr247Ile	missense_variant	11/11	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000401 AC: 10 AN: 249082 Hom.: 0 AF XY: 0.0000371 AC XY: 5 AN XY: 134622

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000497

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1459718 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726160

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2024

The c.998C>T (p.T333I) alteration is located in exon 12 (coding exon 12) of the LUZP2 gene. This alteration results from a C to T substitution at nucleotide position 998, causing the threonine (T) at amino acid position 333 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	0.13
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	2.6
Dann	Uncertain	0.98
DEOGEN2	Benign	0.088	T;.;.
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.55	T;.;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.047	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.7	N;N;.
REVEL	Benign	0.040
Sift	Benign	0.21	T;T;.
Sift4G	Benign	0.29	T;T;T
Polyphen		0.34	B;.;.
Vest4		0.019
MutPred		0.092		Loss of phosphorylation at T333 (P = 0.0243);.;.;
MVP		0.15
MPC		0.14
ClinPred		0.050	T
GERP RS		0.085
Varity_R		0.046
gMVP		0.090

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: rs773564969; hg19: chr11-25100161;