NM_004690.4:c.1937A>G

Variant names:

• chr6-149683152-T-C
• rs1782152084
• NM_004690.4:c.1937A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004690.4(LATS1):​c.1937A>G​(p.His646Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,116 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: 6.8e-7 (0 hom.)
• Consequence: LATS1 NM_004690.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.96
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1937A>G	p.His646Arg	missense	Exon 4 of 8	NP_004681.1	O95835-1
	LATS1	NM_001350339.2		c.1622A>G	p.His541Arg	missense	Exon 5 of 10	NP_001337268.1
	LATS1	NM_001350340.2		c.1622A>G	p.His541Arg	missense	Exon 5 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.1937A>G	p.His646Arg	missense	Exon 4 of 8	ENSP00000437550.1	O95835-1
	LATS1	ENST00000253339.9	TSL:1	c.1937A>G	p.His646Arg	missense	Exon 3 of 7	ENSP00000253339.5	O95835-1
	LATS1	ENST00000392273.7	TSL:1	c.1937A>G	p.His646Arg	missense	Exon 4 of 4	ENSP00000444678.1	O95835-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461116 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726890

African (AFR) AF: 0.0000299 AC: 1 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111436

Other (OTH) AF: 0.00 AC: 0 AN: 60366

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	0.82
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		6.0
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-7.8	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.014	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.78	P
Vest4		0.69
MutPred		0.39		Gain of MoRF binding (P = 0.0184)
MVP		0.85
MPC		2.0
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.88
gMVP		0.57
Mutation Taster		=8/92	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

dbSNP: rs1782152084; hg19: chr6-150004288;