17-18232781-G-T

Variant names:

• chr17-18232781-G-T
• rs772083796
• NM_004140.4:c.371G>T

Variant summary

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

The NM_004140.4(LLGL1):​c.371G>T​(p.Arg124Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,638 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R124Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LLGL1 NM_004140.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.89
• 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.371G>T	p.Arg124Leu	missense	Exon 4 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.371G>T	p.Arg124Leu	missense	Exon 4 of 23	ENSP00000321537.4	Q15334
	LLGL1	ENST00000855607.1		c.371G>T	p.Arg124Leu	missense	Exon 4 of 23	ENSP00000525666.1
	LLGL1	ENST00000855606.1		c.371G>T	p.Arg124Leu	missense	Exon 4 of 23	ENSP00000525665.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461638 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727122

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111982

Other (OTH) AF: 0.00 AC: 0 AN: 60386

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.0084	T
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.9
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.12
Sift	Benign	0.23	T
Sift4G	Benign	0.21	T
Polyphen		0.86	P
Vest4		0.56
MutPred		0.34		Loss of disorder (P = 0.0469)
MVP		0.23
MPC		0.55
ClinPred		0.80	D
GERP RS		5.3
Varity_R		0.23
gMVP		0.59

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: rs772083796; hg19: chr17-18136095;