Variant 17-18225762-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_004140.4(LLGL1):c.80A>G(p.Lys27Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000695 in 990,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00075 ( 0 hom. )

Consequence

LLGL1
NM_004140.4 missense, splice_region

Scores

Splicing: ADA: 0.9993

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.97

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 Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd4 at 50 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LLGL1	NM_004140.4 linkuse as main transcript	c.80A>G	p.Lys27Arg	missense_variant, splice_region_variant	1/23	ENST00000316843.9	NP_004131.4	Q15334

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LLGL1	ENST00000316843.9 linkuse as main transcript	c.80A>G	p.Lys27Arg	missense_variant, splice_region_variant	1/23	1	NM_004140.4	ENSP00000321537.4		Q15334

Frequencies

GnomAD3 genomes

AF:

0.000356

AC:

AN:

140468

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000128

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000210

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000655

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000281

AC:

AN:

17806

Hom.:

AF XY:

0.000266

AC XY:

AN XY:

11266

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000604

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000606

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000751

AC:

638

AN:

849556

Hom.:

Cov.:

AF XY:

0.000779

AC XY:

310

AN XY:

397804

show subpopulations

Gnomad4 AFR exome

AF:

0.000188

Gnomad4 AMR exome

AF:

0.000285

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000790

Gnomad4 OTH exome

AF:

0.00114

GnomAD4 genome

AF:

0.000356

AC:

AN:

140558

Hom.:

Cov.:

AF XY:

0.000353

AC XY:

AN XY:

68084

show subpopulations

Gnomad4 AFR

AF:

0.000128

Gnomad4 AMR

AF:

0.000210

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000655

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000996

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 08, 2023

The c.80A>G (p.K27R) alteration is located in exon 1 (coding exon 1) of the LLGL1 gene. This alteration results from a A to G substitution at nucleotide position 80, causing the lysine (K) at amino acid position 27 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.38

T;.

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.86

M_CAP

Pathogenic

0.99

MetaRNN

Benign

0.24

T;T

MetaSVM

Uncertain

0.15

MutationAssessor

Uncertain

2.2

M;.

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.6

N;.

REVEL

Uncertain

0.33

Sift

Benign

0.15

T;.

Sift4G

Benign

0.19

T;T

Polyphen

0.0010

B;.

Vest4

0.15

MVP

0.84

MPC

0.24

ClinPred

0.068

GERP RS

3.3

Varity_R

0.11

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.91

SpliceAI score (max)

0.020

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