17-18234014-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -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. 13/22 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1216 AD 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

GnomAD3 exomes

AF:

0.00236

AC:

561

AN:

238144

Hom.:

AF XY:

0.00179

AC XY:

231

AN XY:

129014

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 SAS exome

AF:

0.000210

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

Gnomad4 AFR exome

AF:

0.0262

Gnomad4 AMR exome

AF:

0.00225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000102

Gnomad4 SAS exome

AF:

0.000355

Gnomad4 FIN exome

AF:

0.0000392

Gnomad4 NFE exome

AF:

0.000165

Gnomad4 OTH exome

AF:

0.00180

GnomAD4 genome

AF:

0.00798

AC:

1216

AN:

152314

Hom.:

Cov.:

AF XY:

0.00763

AC XY:

568

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0269

Gnomad4 AMR

AF:

0.00438

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00151

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 30, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

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;.

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over