chr6-149684431-T-A

Variant names:

• chr6-149684431-T-A
• rs1326387583
• NM_004690.4:c.658A>T

Variant summary

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

The NM_004690.4(LATS1):​c.658A>T​(p.Ile220Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 32)
• Consequence: LATS1 NM_004690.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.293
• Publications: 0 publications found

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

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=0.05969286).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LATS1	NM_004690.4	c.658A>T	p.Ile220Leu	missense_variant	Exon 4 of 8	ENST00000543571.6	NP_004681.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LATS1	ENST00000543571.6	c.658A>T	p.Ile220Leu	missense_variant	Exon 4 of 8	1	NM_004690.4	ENSP00000437550.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 11, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.658A>T (p.I220L) alteration is located in exon 4 (coding exon 3) of the LATS1 gene. This alteration results from a A to T substitution at nucleotide position 658, causing the isoleucine (I) at amino acid position 220 to be replaced by a leucine (L). 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	0.065
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	5.8
DANN	Benign	0.72
DEOGEN2	Benign	0.16	T;T;.;.
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.76	.;T;T;T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.060	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.76	N;N;N;.
PhyloP100		0.29
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.18	N;N;N;N
REVEL	Benign	0.043
Sift	Benign	0.45	T;T;T;T
Sift4G	Benign	0.86	T;T;T;.
Polyphen		0.0	B;B;B;.
Vest4		0.14
MutPred		0.16		Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);.;
MVP		0.33
MPC		0.073
ClinPred		0.049	T
GERP RS		-1.1
Varity_R		0.042
gMVP		0.080
Mutation Taster		=96/4	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: rs1326387583; hg19: chr6-150005567;