rs200862250

Variant names:

• chrX-65518179-C-T
• rs200862250
• NM_031206.7:c.1735G>A

Variant summary

Our verdict is Benign. The variant received -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. 15/20 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
• Publications: 2 publications found

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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 464822.
• BS2: High Hemizygotes in GnomAd4 at 4 Unknown,XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031206.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAS1L	NM_031206.7	MANE Select	c.1735G>A	p.Val579Ile	missense	Exon 12 of 14	NP_112483.1	Q9Y4W2-1
	LAS1L	NM_001375328.1		c.1735G>A	p.Val579Ile	missense	Exon 12 of 14	NP_001362257.1
	LAS1L	NM_001170649.2		c.1684G>A	p.Val562Ile	missense	Exon 11 of 13	NP_001164120.1	Q9Y4W2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAS1L	ENST00000374811.8	TSL:1 MANE Select	c.1735G>A	p.Val579Ile	missense	Exon 12 of 14	ENSP00000363944.3	Q9Y4W2-1
	LAS1L	ENST00000374807.9	TSL:1	c.1684G>A	p.Val562Ile	missense	Exon 11 of 13	ENSP00000363940.5	Q9Y4W2-2
	LAS1L	ENST00000867035.1		c.1777G>A	p.Val593Ile	missense	Exon 12 of 14	ENSP00000537094.1

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 20 AN: 112046 Hom.: 0 Cov.: 24

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

GnomAD2 exomes AF: 0.000280 AC: 51 AN: 182042 AF XY: 0.000268

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 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

African (AFR) AF: 0.0000762 AC: 2 AN: 26243

American (AMR) AF: 0.00 AC: 0 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.0000517 AC: 1 AN: 19333

East Asian (EAS) AF: 0.00 AC: 0 AN: 30184

South Asian (SAS) AF: 0.00 AC: 0 AN: 53942

European-Finnish (FIN) AF: 0.0000247 AC: 1 AN: 40504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4113

European-Non Finnish (NFE) AF: 0.000611 AC: 510 AN: 834468

Other (OTH) AF: 0.000262 AC: 12 AN: 45830

GnomAD4 genome AF: 0.000178 AC: 20 AN: 112046 Hom.: 0 Cov.: 24 AF XY: 0.000117 AC XY: 4 AN XY: 34208

African (AFR) AF: 0.00 AC: 0 AN: 30783

American (AMR) AF: 0.0000944 AC: 1 AN: 10592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3571

South Asian (SAS) AF: 0.00 AC: 0 AN: 2690

European-Finnish (FIN) AF: 0.000163 AC: 1 AN: 6124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.000338 AC: 18 AN: 53204

Other (OTH) AF: 0.00 AC: 0 AN: 1511

Alfa AF: 0.000304 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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Intellectual disability (1)
-	-	1	not provided (1)
-	1	-	Wilson-Turner syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.025	T
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.39
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.010
Sift	Benign	0.76	T
Sift4G	Uncertain	0.052	T
Polyphen		0.0030	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
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs200862250; hg19: chrX-64738059;