rs200862250

Positions:

chrX-65518179-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_031206.7(LAS1L):c.1735G>A(p.Val579Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000454 in 1,201,865 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 169 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., 4 hem., cov: 24)

Exomes 𝑓: 0.00048 ( 0 hom. 165 hem. )

Consequence

LAS1L
NM_031206.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -0.388

Variant links:

Genes affected

LAS1L (HGNC:25726): (LAS1 like ribosome biogenesis factor) Enables RNA binding activity. Predicted to be involved in maturation of 5.8S rRNA and maturation of LSU-rRNA. Located in membrane. Part of MLL1 complex. Implicated in Wilson-Turner syndrome. [provided by Alliance of Genome Resources, Apr 2022]

LAS1L links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.021074593).

BP6

Variant X-65518179-C-T is Benign according to our data. Variant chrX-65518179-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 464822.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chrX-65518179-C-T is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAS1L	NM_031206.7 linkuse as main transcript	c.1735G>A	p.Val579Ile	missense_variant	12/14	ENST00000374811.8	NP_112483.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAS1L	ENST00000374811.8 linkuse as main transcript	c.1735G>A	p.Val579Ile	missense_variant	12/14	1	NM_031206.7	ENSP00000363944	P2	Q9Y4W2-1

Frequencies

GnomAD3 genomes

AF:

0.000178

AC:

AN:

112046

Hom.:

Cov.:

AF XY:

0.000117

AC XY:

AN XY:

34208

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000944

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000163

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000280

AC:

AN:

182042

Hom.:

AF XY:

0.000268

AC XY:

AN XY:

67246

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000134

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000596

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.000483

AC:

526

AN:

1089819

Hom.:

Cov.:

AF XY:

0.000464

AC XY:

165

AN XY:

355583

show subpopulations

Gnomad4 AFR exome

AF:

0.0000762

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000517

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000247

Gnomad4 NFE exome

AF:

0.000611

Gnomad4 OTH exome

AF:

0.000262

GnomAD4 genome

AF:

0.000178

AC:

AN:

112046

Hom.:

Cov.:

AF XY:

0.000117

AC XY:

AN XY:

34208

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000944

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000163

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000362

Hom.:

Bravo

AF:

0.000212

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.000181

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Wilson-Turner syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 05, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 464822). This variant has not been reported in the literature in individuals affected with LAS1L-related conditions. This variant is present in population databases (rs200862250, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 579 of the LAS1L protein (p.Val579Ile). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2022

LAS1L: BP4, BS2 -

Intellectual disability

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.98

CADD

Benign

2.0

DANN

Benign

0.22

DEOGEN2

Benign

0.025

.;T;.

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.73

T;T;T

M_CAP

Benign

0.0079

MetaRNN

Benign

0.021

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

.;L;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.27

N;N;N

REVEL

Benign

0.010

Sift

Benign

0.76

T;T;T

Sift4G

Uncertain

0.052

T;T;T

Polyphen

0.0030

B;B;B

Vest4

0.050

MVP

0.37

MPC

0.57

ClinPred

0.0097

GERP RS

-1.6

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

3.2

Varity_R

0.038

gMVP

0.068

Splicing

Name

Calibrated prediction

Score

Prediction

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