dbSNP rs28937897: LZTS1:p.Ser29Pro (chr8-20255097-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP5BP4

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. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S29F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

LZTS1
NM_021020.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 3.20

Publications

4 publications found

Variant links:

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]

LZTS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021020.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LZTS1	NM_021020.5	MANE Select	c.85T>C	p.Ser29Pro	missense	Exon 2 of 4	NP_066300.1	Q9Y250-1
	LZTS1	NM_001362884.2		c.85T>C	p.Ser29Pro	missense	Exon 2 of 4	NP_001349813.1	Q9Y250-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LZTS1	ENST00000381569.5	TSL:5 MANE Select	c.85T>C	p.Ser29Pro	missense	Exon 2 of 4	ENSP00000370981.1	Q9Y250-1
LZTS1	ENST00000265801.6	TSL:1	c.85T>C	p.Ser29Pro	missense	Exon 1 of 3	ENSP00000265801.6	Q9Y250-1
LZTS1	ENST00000522290.5	TSL:1	c.85T>C	p.Ser29Pro	missense	Exon 1 of 4	ENSP00000429263.1	Q9Y250-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Esophageal squamous cell carcinoma, somatic (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.066

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.72

M_CAP

Benign

0.0066

MetaRNN

Benign

0.10

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.40

PhyloP100

3.2

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.080

REVEL

Benign

0.065

Sift

Benign

0.27

Sift4G

Benign

0.26

Polyphen

0.0010

Vest4

0.33

MutPred

0.22

Loss of phosphorylation at S29 (P = 0.0097)

MVP

0.34

MPC

1.3

ClinPred

0.92

GERP RS

4.8

PromoterAI

-0.0078

Neutral

(source)

Varity_R

0.13

gMVP

0.53

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over