17-18234014-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004140.4(LLGL1):c.553G>A(p.Val185Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,593,580 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0080 ( 17 hom., cov: 33)

Exomes 𝑓: 0.00090 ( 12 hom. )

Consequence

LLGL1
NM_004140.4 missense, splice_region

Scores

Splicing: ADA: 0.00005714

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.44

Publications

2 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007984072).

BP6

Variant 17-18234014-G-A is Benign according to our data. Variant chr17-18234014-G-A is described in ClinVar as [Benign]. Clinvar id is 720883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00798 (1216/152314) while in subpopulation AFR AF = 0.0269 (1117/41560). AF 95% confidence interval is 0.0256. There are 17 homozygotes in GnomAd4. There are 568 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LLGL1	NM_004140.4 link	c.553G>A	p.Val185Met	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>A	p.Val185Met	missense_variant, splice_region_variant	Exon 6 of 23	1	NM_004140.4	ENSP00000321537.4		Q15334
LLGL1	ENST00000479155.1 link	n.37G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 15	1

Frequencies

GnomAD3 genomes

AF:

0.00799

AC:

1216

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0269

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00438

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.00236

AC:

561

AN:

238144

AF XY:

0.00179

show subpopulations

Gnomad AFR exome

AF:

0.0286

Gnomad AMR exome

AF:

0.00184

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000165

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000298

Gnomad OTH exome

AF:

0.00104

GnomAD4 exome

AF:

0.000899

AC:

1296

AN:

1441266

Hom.:

Cov.:

AF XY:

0.000803

AC XY:

573

AN XY:

713880

show subpopulations

African (AFR)

AF:

0.0262

AC:

868

AN:

33178

American (AMR)

AF:

0.00225

AC:

AN:

43954

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25174

East Asian (EAS)

AF:

0.000102

AC:

AN:

39316

South Asian (SAS)

AF:

0.000355

AC:

AN:

84536

European-Finnish (FIN)

AF:

0.0000392

AC:

AN:

51038

Middle Eastern (MID)

AF:

0.000881

AC:

AN:

5674

European-Non Finnish (NFE)

AF:

0.000165

AC:

181

AN:

1098920

Other (OTH)

AF:

0.00180

AC:

107

AN:

59476

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

164

246

328

410

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00798

AC:

1216

AN:

152314

Hom.:

Cov.:

AF XY:

0.00763

AC XY:

568

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0269

AC:

1117

AN:

41560

American (AMR)

AF:

0.00438

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000294

AC:

AN:

68024

Other (OTH)

AF:

0.00568

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

134

202

269

336

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00193

Hom.:

Bravo

AF:

0.00952

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0343

AC:

151

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00289

AC:

351

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 30, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.44

T;.

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.44

FATHMM_MKL

Uncertain

0.91

MetaRNN

Benign

0.0080

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.6

M;.

PhyloP100

1.4

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.4

N;.

REVEL

Benign

0.050

Sift

Uncertain

0.0030

D;.

Sift4G

Uncertain

0.0050

D;D

Polyphen

0.74

P;.

Vest4

0.41

MVP

0.48

MPC

0.48

ClinPred

0.020

GERP RS

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.040

gMVP

0.43

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000057

dbscSNV1_RF

Benign

0.024

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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17-18234014-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over