chr8-20253576-T-C

Position:

• chr8-20253576-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_021020.5(LZTS1):​c.355A>G​(p.Lys119Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000767 in 1,303,690 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: LZTS1 NM_021020.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.49

Genes affected

LZTS1 (HGNC:13861): (leucine zipper tumor suppressor 1) This gene encodes a tumor suppressor protein that is ubiquitously expressed in normal tissues. In uveal melanomas, expression of this protein is silenced in rapidly metastasizing and metastatic tumor cells but has normal expression in slowly metastasizing or nonmetastasizing tumor cells. This protein may have a role in cell-cycle control by interacting with the Cdk1/cyclinB1 complex. This gene is located on chromosomal region 8p22. Loss of heterozygosity (LOH) in the 8p arm is a common characteristic of many types of cancer. [provided by RefSeq, Nov 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-20253576-T-C is Pathogenic according to our data. Variant chr8-20253576-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 4246.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LZTS1	NM_021020.5	c.355A>G	p.Lys119Glu	missense_variant	3/4	ENST00000381569.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LZTS1	ENST00000381569.5	c.355A>G	p.Lys119Glu	missense_variant	3/4	5	NM_021020.5	P1
LZTS1	ENST00000265801.6	c.355A>G	p.Lys119Glu	missense_variant	2/3	1		P1
LZTS1	ENST00000522290.5	c.355A>G	p.Lys119Glu	missense_variant	2/4	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.67e-7 AC: 1 AN: 1303690 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 633382

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.63e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Esophageal squamous cell carcinoma, somatic Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 30, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;T;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.78	T;.;T
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.51	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.17
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.056	T;T;T
Polyphen		0.92	P;P;D
Vest4		0.79
MutPred		0.11		Loss of ubiquitination at K119 (P = 0.0017);Loss of ubiquitination at K119 (P = 0.0017);Loss of ubiquitination at K119 (P = 0.0017);
MVP		0.39
MPC		1.3
ClinPred		0.95	D
GERP RS		5.3
Varity_R		0.34
gMVP		0.65

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: rs119473032; hg19: chr8-20111087;