Genetic Variant LLGL1:p.Val185Leu (chr17-18234014-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004140.4(LLGL1):c.553G>T(p.Val185Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. V185M) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

LLGL1
NM_004140.4 missense, splice_region

Scores

Splicing: ADA: 0.00002663

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.44

Publications

0 publications found

Variant links:

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)

LLGL1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08404863).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LLGL1	NM_004140.4 link	c.553G>T	p.Val185Leu	missense_variant, splice_region_variant	Exon 6 of 23	ENST00000316843.9	NP_004131.4	Q15334

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LLGL1	ENST00000316843.9 link	c.553G>T	p.Val185Leu	missense_variant, splice_region_variant	Exon 6 of 23	1	NM_004140.4	ENSP00000321537.4		Q15334
LLGL1	ENST00000479155.1 link	n.37G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 15	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.94e-7

AC:

AN:

1441266

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

713880

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33178

American (AMR)

AF:

0.00

AC:

AN:

43954

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25174

East Asian (EAS)

AF:

0.00

AC:

AN:

39316

South Asian (SAS)

AF:

0.0000118

AC:

AN:

84536

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51038

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5674

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1098920

Other (OTH)

AF:

0.00

AC:

AN:

59476

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Benign

0.46

DEOGEN2

Benign

0.30

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.93

FATHMM_MKL

Uncertain

0.91

M_CAP

Benign

0.0041

MetaRNN

Benign

0.084

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.30

N;.

PhyloP100

1.4

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.71

N;.

REVEL

Benign

0.027

Sift

Benign

0.50

T;.

Sift4G

Benign

0.56

T;T

Polyphen

0.0

B;.

Vest4

0.22

MutPred

0.31

Gain of helix (P = 0.132);Gain of helix (P = 0.132);

MVP

0.28

MPC

0.29

ClinPred

0.060

GERP RS

1.1

Varity_R

0.024

gMVP

0.44

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000027

dbscSNV1_RF

Benign

0.0

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over