6-149683420-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The ENST00000543571.6(LATS1):​c.1669C>T​(p.Pro557Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

LATS1
ENST00000543571.6 missense

Scores

7
7
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.36
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 Likely_benign. Variant got -4 ACMG points.

BS2
High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LATS1NM_004690.4 linkuse as main transcriptc.1669C>T p.Pro557Ser missense_variant 4/8 ENST00000543571.6 NP_004681.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LATS1ENST00000543571.6 linkuse as main transcriptc.1669C>T p.Pro557Ser missense_variant 4/81 NM_004690.4 ENSP00000437550 P1O95835-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251452
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135898
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:
0.0000116
AC:
17
AN:
1461892
Hom.:
0
Cov.:
32
AF XY:
0.0000138
AC XY:
10
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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:
0.0000144
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000312
Hom.:
0
Bravo
AF:
0.00000378
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
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 10, 2023The c.1669C>T (p.P557S) alteration is located in exon 4 (coding exon 3) of the LATS1 gene. This alteration results from a C to T substitution at nucleotide position 1669, causing the proline (P) at amino acid position 557 to be replaced by a serine (S). 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
Pathogenic
0.79
BayesDel_addAF
Uncertain
0.053
T
BayesDel_noAF
Benign
-0.16
CADD
Pathogenic
26
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.74
D;D;.
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
.;D;D
M_CAP
Benign
0.026
D
MetaRNN
Uncertain
0.46
T;T;T
MetaSVM
Benign
-0.65
T
MutationAssessor
Uncertain
2.5
M;M;M
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.69
T
PROVEAN
Pathogenic
-5.9
D;D;D
REVEL
Uncertain
0.31
Sift
Benign
0.039
D;D;D
Sift4G
Uncertain
0.0060
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.53
MutPred
0.26
Loss of catalytic residue at P557 (P = 0.0231);Loss of catalytic residue at P557 (P = 0.0231);Loss of catalytic residue at P557 (P = 0.0231);
MVP
0.64
MPC
0.43
ClinPred
0.99
D
GERP RS
5.5
Varity_R
0.25
gMVP
0.37

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: rs749182673; hg19: chr6-150004556; COSMIC: COSV53601028; COSMIC: COSV53601028; API