6-149661912-A-T

Variant summary

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

The NM_004690.4(LATS1):​c.3210T>A​(p.His1070Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,864 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

LATS1
NM_004690.4 missense

Scores

1
10
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.35
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 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LATS1NM_004690.4 linkc.3210T>A p.His1070Gln missense_variant Exon 8 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.3210T>A p.His1070Gln missense_variant Exon 8 of 8 1 NM_004690.4 ENSP00000437550.1 O95835-1
LATS1ENST00000253339.9 linkc.3210T>A p.His1070Gln missense_variant Exon 7 of 7 1 ENSP00000253339.5 O95835-1
LATS1ENST00000441107.5 linkn.*2897T>A non_coding_transcript_exon_variant Exon 9 of 9 1 ENSP00000403815.1 Q6PJG3
LATS1ENST00000441107.5 linkn.*2897T>A 3_prime_UTR_variant Exon 9 of 9 1 ENSP00000403815.1 Q6PJG3

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152180
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251092
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135694
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:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461684
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727128
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:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152180
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74340
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Nov 09, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.3210T>A (p.H1070Q) alteration is located in exon 8 (coding exon 7) of the LATS1 gene. This alteration results from a T to A substitution at nucleotide position 3210, causing the histidine (H) at amino acid position 1070 to be replaced by a glutamine (Q). 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
0.98
BayesDel_addAF
Uncertain
0.099
D
BayesDel_noAF
Benign
-0.090
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.58
D;D
Eigen
Benign
0.037
Eigen_PC
Benign
0.13
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.91
.;D
M_CAP
Benign
0.034
D
MetaRNN
Uncertain
0.47
T;T
MetaSVM
Benign
-0.98
T
MutationAssessor
Uncertain
2.3
M;M
PrimateAI
Uncertain
0.77
T
PROVEAN
Uncertain
-3.6
D;D
REVEL
Benign
0.22
Sift
Uncertain
0.017
D;D
Sift4G
Benign
0.19
T;T
Polyphen
0.27
B;B
Vest4
0.61
MutPred
0.40
Gain of ubiquitination at K1066 (P = 0.1028);Gain of ubiquitination at K1066 (P = 0.1028);
MVP
0.88
MPC
1.4
ClinPred
0.80
D
GERP RS
3.7
Varity_R
0.31
gMVP
0.78

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: rs746667858; hg19: chr6-149983048; API