6-149683498-G-A

Position:

• chr6-149683498-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000543571.6(LATS1):​c.1591C>T​(p.Pro531Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00719 in 1,614,200 control chromosomes in the GnomAD database, including 61 homozygotes. 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 Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0047 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0074 (58 hom.)
• Consequence: LATS1 ENST00000543571.6 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.69

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005334854).
• BP6: Variant 6-149683498-G-A is Benign according to our data. Variant chr6-149683498-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 719906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 713 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LATS1	NM_004690.4	c.1591C>T	p.Pro531Ser	missense_variant	4/8	ENST00000543571.6	NP_004681.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LATS1	ENST00000543571.6	c.1591C>T	p.Pro531Ser	missense_variant	4/8	1	NM_004690.4	ENSP00000437550	P1

Frequencies

GnomAD3 genomes AF: 0.00468 AC: 713 AN: 152198 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00462

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00780

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00414 AC: 1040 AN: 251482 Hom.: 1 AF XY: 0.00397 AC XY: 539 AN XY: 135914

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00319

Gnomad NFE exome AF: 0.00711

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00745 AC: 10890 AN: 1461884 Hom.: 58 Cov.: 32 AF XY: 0.00715 AC XY: 5199 AN XY: 727246

Gnomad4 AFR exome AF: 0.00116

Gnomad4 AMR exome AF: 0.00266

Gnomad4 ASJ exome AF: 0.000842

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00354

Gnomad4 NFE exome AF: 0.00904

Gnomad4 OTH exome AF: 0.00763

GnomAD4 genome AF: 0.00468 AC: 713 AN: 152316 Hom.: 3 Cov.: 32 AF XY: 0.00459 AC XY: 342 AN XY: 74470

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00462

Gnomad4 NFE AF: 0.00780

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00645 Hom.: 6

Bravo AF: 0.00424

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.00986 AC: 38

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00744 AC: 64

ExAC AF: 0.00380 AC: 461

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00736

EpiControl AF: 0.00664

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 30, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T;T;.
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	.;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0053	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.2	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.081	T;T;T
Polyphen		0.0050	B;B;B
Vest4		0.21
MVP		0.71
MPC		0.096
ClinPred		0.021	T
GERP RS		5.5
Varity_R		0.087
gMVP		0.17

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

Other links and lift over

dbSNP: rs55874734; hg19: chr6-150004634;