chr6-149676333-C-T

Variant names:

• chr6-149676333-C-T
• NM_004690.4:c.2810G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004690.4(LATS1):​c.2810G>A​(p.Gly937Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 7.57
• 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_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004690.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LATS1	NM_004690.4	MANE Select	c.2810G>A	p.Gly937Asp	missense	Exon 7 of 8	NP_004681.1	O95835-1
	LATS1	NM_001350339.2		c.2495G>A	p.Gly832Asp	missense	Exon 8 of 10	NP_001337268.1
	LATS1	NM_001350340.2		c.2495G>A	p.Gly832Asp	missense	Exon 8 of 9	NP_001337269.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LATS1	ENST00000543571.6	TSL:1 MANE Select	c.2810G>A	p.Gly937Asp	missense	Exon 7 of 8	ENSP00000437550.1	O95835-1
	LATS1	ENST00000253339.9	TSL:1	c.2810G>A	p.Gly937Asp	missense	Exon 6 of 7	ENSP00000253339.5	O95835-1
	LATS1	ENST00000441107.5	TSL:1	n.*2497G>A		non_coding_transcript_exon	Exon 8 of 9	ENSP00000403815.1	Q6PJG3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		7.6
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.90		Gain of catalytic residue at G937 (P = 0.1366)
MVP		0.90
MPC		2.0
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.90
gMVP		0.99
Mutation Taster		=9/91	disease causing

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

hg19: chr6-149997469;