10-101002864-A-G

Variant names:

• chr10-101002864-A-G
• rs779700700
• NM_001318100.2:c.326A>G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001318100.2(LZTS2):​c.326A>G​(p.Asp109Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000496 in 1,613,748 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000051 (1 hom.)
• Consequence: LZTS2 NM_001318100.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.25

Genes affected

LZTS2 (HGNC:29381): (leucine zipper tumor suppressor 2) The protein encoded by this gene belongs to the leucine zipper tumor suppressor family of proteins, which function in transcription regulation and cell cycle control. This family member can repress beta-catenin-mediated transcriptional activation and is a negative regulator of the Wnt signaling pathway. It negatively regulates microtubule severing at centrosomes, and is necessary for central spindle formation and cytokinesis completion. It is implicated in cancer, where it may inhibit cell proliferation and decrease susceptibility to tumor development. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18793729).
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LZTS2	NM_001318100.2	c.326A>G	p.Asp109Gly	missense_variant	Exon 2 of 5	ENST00000454422.2	NP_001305029.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LZTS2	ENST00000454422.2	c.326A>G	p.Asp109Gly	missense_variant	Exon 2 of 5	2	NM_001318100.2	ENSP00000416972.2

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251214 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135830

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000513 AC: 75 AN: 1461508 Hom.: 1 Cov.: 32 AF XY: 0.0000564 AC XY: 41 AN XY: 727062

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000621

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74376

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.326A>G (p.D109G) alteration is located in exon 2 (coding exon 1) of the LZTS2 gene. This alteration results from a A to G substitution at nucleotide position 326, causing the aspartic acid (D) at amino acid position 109 to be replaced by a glycine (G). 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	0.11
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.035	T;T;T;.;T;.
Eigen	Benign	0.071
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.82	T;.;T;T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.19	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	.;L;.;.;L;.
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.2	N;N;N;.;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.020	D;D;D;.;D;D
Sift4G	Benign	0.18	T;T;D;D;T;D
Polyphen		0.46	.;P;.;.;P;.
Vest4		0.17, 0.10
MutPred		0.22		Loss of helix (P = 0.0017);Loss of helix (P = 0.0017);Loss of helix (P = 0.0017);Loss of helix (P = 0.0017);Loss of helix (P = 0.0017);Loss of helix (P = 0.0017);
MVP		0.34
MPC		0.68
ClinPred		0.27	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.22
gMVP		0.29

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: rs779700700; hg19: chr10-102762621;