rs200862250

chrX-65518179-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.388

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]

ACMG classification

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: {Uncertain_significance=1, Likely_benign=1}. Variant chrX-65518179-C-T is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAS1L	NM_031206.7	c.1735G>A	p.Val579Ile	missense_variant	12/14	ENST00000374811.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAS1L	ENST00000374811.8	c.1735G>A	p.Val579Ile	missense_variant	12/14	1	NM_031206.7	P2

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 20 AN: 112046 Hom.: 0 Cov.: 24 AF XY: 0.000117 AC XY: 4 AN XY: 34208

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: 51 AN: 182042 Hom.: 0 AF XY: 0.000268 AC XY: 18 AN XY: 67246

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.: 0 Cov.: 29 AF XY: 0.000464 AC XY: 165 AN XY: 355583

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: 20 AN: 112046 Hom.: 0 Cov.: 24 AF XY: 0.000117 AC XY: 4 AN XY: 34208

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.: 3

Bravo AF: 0.000212

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.000545

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Wilson-Turner syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

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	T
BayesDel_noAF	Benign	-0.98
Cadd	Benign	2.0
Dann	Benign	0.22
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.73	T;T;T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.021	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.29	T
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	T
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

Other links and lift over

dbSNP: rs200862250; hg19: chrX-64738059;