NM_004140.4:c.52C>G

Variant names:

• chr17-18225734-C-G
• rs779701944
• NM_004140.4:c.52C>G

Variant summary

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

The NM_004140.4(LLGL1):​c.52C>G​(p.Leu18Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000683 in 146,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LLGL1 NM_004140.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.01
• Publications: 0 publications found

Genes affected

LLGL1 (HGNC:6628): (LLGL scribble cell polarity complex component 1) This gene encodes a protein that is similar to a tumor suppressor in Drosophila. The protein is part of a cytoskeletal network and is associated with nonmuscle myosin II heavy chain and a kinase that specifically phosphorylates this protein at serine residues. The gene is located within the Smith-Magenis syndrome region on chromosome 17. [provided by RefSeq, Jul 2008]

LLGL1 Gene-Disease associations (from GenCC):

• Tourette syndrome

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

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_004140.4. 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
	LLGL1	NM_004140.4	MANE Select	c.52C>G	p.Leu18Val	missense	Exon 1 of 23	NP_004131.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LLGL1	ENST00000316843.9	TSL:1 MANE Select	c.52C>G	p.Leu18Val	missense	Exon 1 of 23	ENSP00000321537.4	Q15334
	LLGL1	ENST00000855607.1		c.52C>G	p.Leu18Val	missense	Exon 1 of 23	ENSP00000525666.1
	LLGL1	ENST00000855606.1		c.52C>G	p.Leu18Val	missense	Exon 1 of 23	ENSP00000525665.1

Frequencies

GnomAD3 genomes AF: 0.00000683 AC: 1 AN: 146348 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

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: 0.000496

GnomAD2 exomes AF: 0.00 AC: 0 AN: 40996 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 912540 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 432730

African (AFR) AF: 0.00 AC: 0 AN: 17252

American (AMR) AF: 0.00 AC: 0 AN: 7016

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9944

East Asian (EAS) AF: 0.00 AC: 0 AN: 6690

South Asian (SAS) AF: 0.00 AC: 0 AN: 32222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1998

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 800960

Other (OTH) AF: 0.00 AC: 0 AN: 30546

GnomAD4 genome AF: 0.00000683 AC: 1 AN: 146348 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 71198

African (AFR) AF: 0.00 AC: 0 AN: 40804

American (AMR) AF: 0.00 AC: 0 AN: 14758

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3392

East Asian (EAS) AF: 0.00 AC: 0 AN: 5084

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8430

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65840

Other (OTH) AF: 0.000496 AC: 1 AN: 2018

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000584 AC: 3

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	Benign	0.096
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.67	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.24	T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	1.9	L
PhyloP100		1.0
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.31
Sift	Benign	0.057	T
Sift4G	Benign	0.088	T
Polyphen		0.0030	B
Vest4		0.20
MutPred		0.50		Gain of methylation at K17 (P = 0.034)
MVP		0.34
MPC		0.30
ClinPred		0.10	T
GERP RS		2.4
PromoterAI		0.20	Neutral
Varity_R		0.16
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.27		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs779701944; hg19: chr17-18129048;