Genetic Variant LLGL1:p.Asn35Ser (chr17-18229963-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -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. 15/20 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

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=0.007491708).

BP6

Variant 17-18229963-A-G is Benign according to our data. Variant chr17-18229963-A-G is described in ClinVar as [Benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1577 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LLGL1	NM_004140.4 link	c.104A>G	p.Asn35Ser	missense_variant	Exon 2 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.104A>G	p.Asn35Ser	missense_variant	Exon 2 of 23	1	NM_004140.4	ENSP00000321537.4		Q15334

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

GnomAD3 exomes

AF:

0.00522

AC:

1296

AN:

248150

Hom.:

AF XY:

0.00520

AC XY:

699

AN XY:

134322

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 SAS exome

AF:

0.00439

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

Gnomad4 AFR exome

AF:

0.0271

Gnomad4 AMR exome

AF:

0.00440

Gnomad4 ASJ exome

AF:

0.00978

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.00443

Gnomad4 FIN exome

AF:

0.00112

Gnomad4 NFE exome

AF:

0.00210

Gnomad4 OTH exome

AF:

0.00582

GnomAD4 genome

AF:

0.0104

AC:

1577

AN:

152254

Hom.:

Cov.:

AF XY:

0.0102

AC XY:

761

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0272

Gnomad4 AMR

AF:

0.00810

Gnomad4 ASJ

AF:

0.00979

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00436

Gnomad4 FIN

AF:

0.00198

Gnomad4 NFE

AF:

0.00315

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.00367

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Oct 24, 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

0.055

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.44

T;.

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.27

FATHMM_MKL

Uncertain

0.95

MetaRNN

Benign

0.0075

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.095

N;.

PrimateAI

Benign

0.43

PROVEAN

Benign

-2.0

N;.

REVEL

Benign

0.11

Sift

Benign

0.12

T;.

Sift4G

Benign

0.12

T;T

Polyphen

0.010

B;.

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

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

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