NM_004140.4:c.104A>G

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.104A>G(p.Asn35Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00386 in 1,610,546 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 16 hom., cov: 33)

Exomes 𝑓: 0.0032 ( 27 hom. )

Consequence

LLGL1
NM_004140.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.14

Publications

6 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=0.007491708).

BP6

Variant 17-18229963-A-G is Benign according to our data. Variant chr17-18229963-A-G is described in ClinVar as Benign. ClinVar VariationId is 777136.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 = 0.0104 (1577/152254) while in subpopulation AFR AF = 0.0272 (1129/41548). AF 95% confidence interval is 0.0259. There are 16 homozygotes in GnomAd4. There are 761 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 16 Unknown gene

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.104A>G	p.Asn35Ser	missense	Exon 2 of 23	NP_004131.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LLGL1	ENST00000316843.9	TSL:1 MANE Select	c.104A>G	p.Asn35Ser	missense	Exon 2 of 23	ENSP00000321537.4	Q15334
LLGL1	ENST00000855607.1		c.104A>G	p.Asn35Ser	missense	Exon 2 of 23	ENSP00000525666.1
LLGL1	ENST00000855606.1		c.104A>G	p.Asn35Ser	missense	Exon 2 of 23	ENSP00000525665.1

Frequencies

GnomAD3 genomes

AF:

0.0104

AC:

1575

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0272

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00812

Gnomad ASJ

AF:

0.00979

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00394

Gnomad FIN

AF:

0.00198

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00315

Gnomad OTH

AF:

0.0125

GnomAD2 exomes

AF:

0.00522

AC:

1296

AN:

248150

AF XY:

0.00520

show subpopulations

Gnomad AFR exome

AF:

0.0280

Gnomad AMR exome

AF:

0.00386

Gnomad ASJ exome

AF:

0.00929

Gnomad EAS exome

AF:

0.0000547

Gnomad FIN exome

AF:

0.00127

Gnomad NFE exome

AF:

0.00352

Gnomad OTH exome

AF:

0.00996

GnomAD4 exome

AF:

0.00318

AC:

4635

AN:

1458292

Hom.:

Cov.:

AF XY:

0.00325

AC XY:

2358

AN XY:

725534

show subpopulations

African (AFR)

AF:

0.0271

AC:

905

AN:

33428

American (AMR)

AF:

0.00440

AC:

196

AN:

44512

Ashkenazi Jewish (ASJ)

AF:

0.00978

AC:

255

AN:

26068

East Asian (EAS)

AF:

0.000202

AC:

AN:

39618

South Asian (SAS)

AF:

0.00443

AC:

381

AN:

85922

European-Finnish (FIN)

AF:

0.00112

AC:

AN:

51756

Middle Eastern (MID)

AF:

0.0253

AC:

143

AN:

5656

European-Non Finnish (NFE)

AF:

0.00210

AC:

2338

AN:

1111044

Other (OTH)

AF:

0.00582

AC:

351

AN:

60288

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

185

369

554

738

923

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

180

270

360

450

<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

AF:

0.0104

AC:

1577

AN:

152254

Hom.:

Cov.:

AF XY:

0.0102

AC XY:

761

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0272

AC:

1129

AN:

41548

American (AMR)

AF:

0.00810

AC:

124

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00979

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.00436

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00198

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00315

AC:

214

AN:

68004

Other (OTH)

AF:

0.0123

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

142

212

283

354

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00578

Hom.:

Bravo

AF:

0.0125

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.0256

AC:

113

ESP6500EA

AF:

0.00384

AC:

ExAC

AF:

0.00562

AC:

682

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.00532

EpiControl

AF:

0.00513

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.44

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.27

FATHMM_MKL

Uncertain

0.95

MetaRNN

Benign

0.0075

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.095

PhyloP100

3.1

PrimateAI

Benign

0.43

PROVEAN

Benign

-2.0

REVEL

Benign

0.11

Sift

Benign

0.12

Sift4G

Benign

0.12

Polyphen

0.010

Vest4

0.23

MVP

0.38

MPC

0.24

ClinPred

0.0088

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.090

gMVP

0.27

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over