rs867562406

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_031206.7(LAS1L):c.1082C>G(p.Pro361Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000495 in 525,110 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P361P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000058 ( 0 hom. 12 hem. )

Consequence

LAS1L
NM_031206.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.928

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 Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06995916).

BP6

Variant X-65524575-G-C is Benign according to our data. Variant chrX-65524575-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 464820.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chrX-65524575-G-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAS1L	NM_031206.7 linkuse as main transcript	c.1082C>G	p.Pro361Arg	missense_variant	9/14	ENST00000374811.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAS1L	ENST00000374811.8 linkuse as main transcript	c.1082C>G	p.Pro361Arg	missense_variant	9/14	1	NM_031206.7	P2	Q9Y4W2-1

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111689

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

33883

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00847

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000581

AC:

AN:

413367

Hom.:

Cov.:

AF XY:

0.0000788

AC XY:

AN XY:

152349

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000342

Gnomad4 OTH exome

AF:

0.0000860

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111743

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

33947

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Wilson-Turner syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 05, 2019

This variant has not been reported in the literature in individuals with LAS1L-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with arginine at codon 361 of the LAS1L protein (p.Pro361Arg). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and arginine. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

LAS1L: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.49

Cadd

Benign

Dann

Benign

0.95

DEOGEN2

Benign

0.048

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.65

M_CAP

Benign

0.0051

MetaRNN

Benign

0.070

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.5

MutationTaster

Benign

0.96

D;D;D;N

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.5

REVEL

Benign

0.047

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0040

Polyphen

0.0020

Vest4

0.19

MutPred

0.16

Gain of phosphorylation at S363 (P = 0.0779);

MVP

0.14

MPC

0.93

ClinPred

0.23

GERP RS

0.70

Varity_R

0.26

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.20

Position offset: 39

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