rs28937897

Positions:

• chr8-20255097-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_021020.5(LZTS1):​c.85T>C​(p.Ser29Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LZTS1 NM_021020.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.20

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-20255097-A-G is Pathogenic according to our data. Variant chr8-20255097-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 4245.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.100833565). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LZTS1	NM_021020.5	c.85T>C	p.Ser29Pro	missense_variant	2/4	ENST00000381569.5	NP_066300.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LZTS1	ENST00000381569.5	c.85T>C	p.Ser29Pro	missense_variant	2/4	5	NM_021020.5	ENSP00000370981	P1
LZTS1	ENST00000265801.6	c.85T>C	p.Ser29Pro	missense_variant	1/3	1		ENSP00000265801	P1
LZTS1	ENST00000522290.5	c.85T>C	p.Ser29Pro	missense_variant	1/4	1		ENSP00000429263

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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	0.16
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.066	T;T;.;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.72	T;.;T;T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.10	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.40	N;N;N;N
MutationTaster	Benign	0.89	D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.080	N;N;N;.
REVEL	Benign	0.065
Sift	Benign	0.27	T;T;T;.
Sift4G	Benign	0.26	T;T;T;T
Polyphen		0.0010	B;B;B;.
Vest4		0.33
MutPred		0.22		Loss of phosphorylation at S29 (P = 0.0097);Loss of phosphorylation at S29 (P = 0.0097);Loss of phosphorylation at S29 (P = 0.0097);Loss of phosphorylation at S29 (P = 0.0097);
MVP		0.34
MPC		1.3
ClinPred		0.92	D
GERP RS		4.8
Varity_R		0.13
gMVP		0.53

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: rs28937897; hg19: chr8-20112608;