17-18225734-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004140.4(LLGL1):​c.52C>T​(p.Leu18Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000011 in 912,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L18V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: LLGL1 NM_004140.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2866128).

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>T	p.Leu18Phe	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>T	p.Leu18Phe	missense	Exon 1 of 23	ENSP00000321537.4	Q15334
	LLGL1	ENST00000855607.1		c.52C>T	p.Leu18Phe	missense	Exon 1 of 23	ENSP00000525666.1
	LLGL1	ENST00000855606.1		c.52C>T	p.Leu18Phe	missense	Exon 1 of 23	ENSP00000525665.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000110 AC: 1 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: 0.000149 AC: 1 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 Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.67	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	0.40	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		1.0
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.035	D
Polyphen		0.090	B
Vest4		0.23
MutPred		0.49		Gain of methylation at K17 (P = 0.0293)
MVP		0.53
MPC		0.42
ClinPred		0.82	D
GERP RS		2.4
PromoterAI		-0.012	Neutral
Varity_R		0.25
gMVP		0.36
Mutation Taster		=75/25	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: rs779701944; hg19: chr17-18129048;