NM_021020.5:c.1741C>G

Variant names:

• chr8-20249772-G-C
• rs781638695
• NM_021020.5:c.1741C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021020.5(LZTS1):​c.1741C>G​(p.Leu581Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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: 0.0000021 (0 hom.)
• Consequence: LZTS1 NM_021020.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.48
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0669629).

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.1741C>G	p.Leu581Val	missense	Exon 4 of 4	NP_066300.1	Q9Y250-1
	LZTS1	NM_001362884.2		c.1741C>G	p.Leu581Val	missense	Exon 4 of 4	NP_001349813.1	Q9Y250-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LZTS1	ENST00000381569.5	TSL:5 MANE Select	c.1741C>G	p.Leu581Val	missense	Exon 4 of 4	ENSP00000370981.1	Q9Y250-1
	LZTS1	ENST00000265801.6	TSL:1	c.1741C>G	p.Leu581Val	missense	Exon 3 of 3	ENSP00000265801.6	Q9Y250-1
	LZTS1	ENST00000522290.5	TSL:1	c.1564C>G	p.Leu522Val	missense	Exon 4 of 4	ENSP00000429263.1	Q9Y250-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250810 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460932 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726840

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111960

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.5
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.021
Sift	Uncertain	0.026	D
Sift4G	Benign	0.56	T
Polyphen		0.0080	B
Vest4		0.068
MutPred		0.27		Loss of disorder (P = 0.2395)
MVP		0.33
MPC		0.40
ClinPred		0.091	T
GERP RS		3.1
Varity_R		0.051
gMVP		0.24
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs781638695; hg19: chr8-20107283;