6-149683546-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004690.4(LATS1):ā€‹c.1543A>Gā€‹(p.Thr515Ala) 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 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

LATS1
NM_004690.4 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.19
Variant links:
Genes affected
LATS1 (HGNC:6514): (large tumor suppressor kinase 1) The protein encoded by this gene is a putative serine/threonine kinase that localizes to the mitotic apparatus and complexes with cell cycle controller CDC2 kinase in early mitosis. The protein is phosphorylated in a cell-cycle dependent manner, with late prophase phosphorylation remaining through metaphase. The N-terminal region of the protein binds CDC2 to form a complex showing reduced H1 histone kinase activity, indicating a role as a negative regulator of CDC2/cyclin A. In addition, the C-terminal kinase domain binds to its own N-terminal region, suggesting potential negative regulation through interference with complex formation via intramolecular binding. Biochemical and genetic data suggest a role as a tumor suppressor. This is supported by studies in knockout mice showing development of soft-tissue sarcomas, ovarian stromal cell tumors and a high sensitivity to carcinogenic treatments. [provided by RefSeq, Apr 2017]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.16000482).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LATS1NM_004690.4 linkc.1543A>G p.Thr515Ala missense_variant Exon 4 of 8 ENST00000543571.6 NP_004681.1 O95835-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LATS1ENST00000543571.6 linkc.1543A>G p.Thr515Ala missense_variant Exon 4 of 8 1 NM_004690.4 ENSP00000437550.1 O95835-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251488
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135920
show subpopulations
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461892
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727248
show subpopulations
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 12, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1543A>G (p.T515A) alteration is located in exon 4 (coding exon 3) of the LATS1 gene. This alteration results from a A to G substitution at nucleotide position 1543, causing the threonine (T) at amino acid position 515 to be replaced by an alanine (A). 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
0.067
BayesDel_addAF
Uncertain
0.059
T
BayesDel_noAF
Benign
-0.15
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.27
T;T;.
Eigen
Benign
0.069
Eigen_PC
Uncertain
0.23
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.85
.;T;T
M_CAP
Benign
0.0083
T
MetaRNN
Benign
0.16
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.69
N;N;N
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-1.2
N;N;N
REVEL
Benign
0.14
Sift
Benign
0.24
T;T;T
Sift4G
Benign
0.61
T;T;T
Polyphen
0.0090
B;B;P
Vest4
0.16
MutPred
0.075
Gain of glycosylation at P514 (P = 0.0965);Gain of glycosylation at P514 (P = 0.0965);Gain of glycosylation at P514 (P = 0.0965);
MVP
0.76
MPC
0.075
ClinPred
0.23
T
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.11
gMVP
0.40

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs776825053; hg19: chr6-150004682; API