rs371394378

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_031206.7(LAS1L):c.1892G>C(p.Gly631Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000488 in 1,208,726 control chromosomes in the GnomAD database, including 1 homozygotes. There are 16 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G631G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.000050 ( 1 hom. 15 hem. )

Consequence

LAS1L
NM_031206.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.55

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.047071785).

BS2

High Hemizygotes in GnomAdExome at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAS1L	NM_031206.7 linkuse as main transcript	c.1892G>C	p.Gly631Ala	missense_variant	12/14	ENST00000374811.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAS1L	ENST00000374811.8 linkuse as main transcript	c.1892G>C	p.Gly631Ala	missense_variant	12/14	1	NM_031206.7	P2	Q9Y4W2-1

Frequencies

GnomAD3 genomes

AF:

0.0000355

AC:

AN:

112632

Hom.:

Cov.:

AF XY:

0.0000287

AC XY:

AN XY:

34786

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:

0.00

Gnomad NFE

AF:

0.0000751

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000170

AC:

AN:

176921

Hom.:

AF XY:

0.0000317

AC XY:

AN XY:

63025

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000384

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000502

AC:

AN:

1096094

Hom.:

Cov.:

AF XY:

0.0000415

AC XY:

AN XY:

361832

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:

0.0000618

Gnomad4 OTH exome

AF:

0.0000652

GnomAD4 genome

AF:

0.0000355

AC:

AN:

112632

Hom.:

Cov.:

AF XY:

0.0000287

AC XY:

AN XY:

34786

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:

0.0000751

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.1892G>C (p.G631A) alteration is located in exon 12 (coding exon 12) of the LAS1L gene. This alteration results from a G to C substitution at nucleotide position 1892, causing the glycine (G) at amino acid position 631 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Wilson-Turner syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 20, 2022

This variant is present in population databases (rs371394378, gnomAD 0.005%). 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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 464823). This variant has not been reported in the literature in individuals affected with LAS1L-related conditions. This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 631 of the LAS1L protein (p.Gly631Ala). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.63

Cadd

Benign

Dann

Benign

0.27

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.83

T;T;T

M_CAP

Benign

0.064

MetaRNN

Benign

0.047

T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

D;N;N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

0.20

N;N;N

REVEL

Benign

0.047

Sift

Benign

1.0

T;T;T

Sift4G

Benign

0.96

T;T;T

Polyphen

0.063

B;B;B

Vest4

0.10

MutPred

0.15

.;Gain of helix (P = 0.0117);.;

MVP

0.48

MPC

0.69

ClinPred

0.038

GERP RS

2.6

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

3.9

Varity_R

0.050

gMVP

0.086

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