Genetic Variant NM_031206.7:c.1472G>A (chrX-65518442-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_031206.7(LAS1L):c.1472G>A(p.Gly491Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

LAS1L
NM_031206.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.13

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Wilson-Turner syndrome
Inheritance: XL Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P
spinal muscular atrophy with respiratory distress type 2
Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet
X-linked syndromic intellectual disability
Inheritance: XL Classification: LIMITED Submitted by: ClinGen

LAS1L links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06363624).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAS1L	NM_031206.7 link	c.1472G>A	p.Gly491Asp	missense_variant	Exon 12 of 14	ENST00000374811.8	NP_112483.1	Q9Y4W2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAS1L	ENST00000374811.8 link	c.1472G>A	p.Gly491Asp	missense_variant	Exon 12 of 14	1	NM_031206.7	ENSP00000363944.3		Q9Y4W2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1089993

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

356655

African (AFR)

AF:

0.00

AC:

AN:

26203

American (AMR)

AF:

0.00

AC:

AN:

34701

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18995

East Asian (EAS)

AF:

0.00

AC:

AN:

30108

South Asian (SAS)

AF:

0.00

AC:

AN:

53122

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39561

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3625

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

837991

Other (OTH)

AF:

0.00

AC:

AN:

45687

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Wilson-Turner syndrome

Uncertain:1

Dec 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 491 of the LAS1L protein (p.Gly491Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LAS1L-related conditions. ClinVar contains an entry for this variant (Variation ID: 533407). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LAS1L protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.020

.;T;.

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.82

T;T;T

M_CAP

Benign

0.0044

MetaRNN

Benign

0.064

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

.;N;.

PhyloP100

1.1

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.17

N;N;N

REVEL

Benign

0.039

Sift

Benign

0.53

T;T;T

Sift4G

Benign

0.62

T;T;T

Polyphen

0.21

B;P;B

Vest4

0.084

MutPred

0.25

.;Gain of loop (P = 0.0851);.;

MVP

0.12

MPC

0.93

ClinPred

0.069

GERP RS

-1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.075

gMVP

0.34

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over