X-65518409-C-T

Variant names:

• chrX-65518409-C-T
• rs202068829
• NM_031206.7:c.1505G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_031206.7(LAS1L):​c.1505G>A​(p.Arg502His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000141 in 1,209,711 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R502P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 0 hem., cov: 24)
  • Exomes 𝑓: 0.000013 (0 hom. 6 hem.)
• Consequence: LAS1L NM_031206.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.450
• Publications: 3 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.032875627).
• BS2: High Hemizygotes in GnomAdExome4 at 6 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.1505G>A	p.Arg502His	missense	Exon 12 of 14	NP_112483.1	Q9Y4W2-1
	LAS1L	NM_001375328.1		c.1505G>A	p.Arg502His	missense	Exon 12 of 14	NP_001362257.1
	LAS1L	NM_001170649.2		c.1454G>A	p.Arg485His	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.1505G>A	p.Arg502His	missense	Exon 12 of 14	ENSP00000363944.3	Q9Y4W2-1
	LAS1L	ENST00000374807.9	TSL:1	c.1454G>A	p.Arg485His	missense	Exon 11 of 13	ENSP00000363940.5	Q9Y4W2-2
	LAS1L	ENST00000867035.1		c.1547G>A	p.Arg516His	missense	Exon 12 of 14	ENSP00000537094.1

Frequencies

GnomAD3 genomes AF: 0.0000266 AC: 3 AN: 112964 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000643

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: 0.0000187

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000329 AC: 6 AN: 182111 AF XY: 0.0000300

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.0000366

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000369

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000128 AC: 14 AN: 1096694 Hom.: 0 Cov.: 32 AF XY: 0.0000166 AC XY: 6 AN XY: 362148

African (AFR) AF: 0.0000379 AC: 1 AN: 26374

American (AMR) AF: 0.000114 AC: 4 AN: 35146

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19326

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30183

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 53991

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40361

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3993

European-Non Finnish (NFE) AF: 0.00000713 AC: 6 AN: 841309

Other (OTH) AF: 0.0000217 AC: 1 AN: 46011

GnomAD4 genome AF: 0.0000265 AC: 3 AN: 113017 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 35185

African (AFR) AF: 0.0000642 AC: 2 AN: 31174

American (AMR) AF: 0.00 AC: 0 AN: 10727

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2667

East Asian (EAS) AF: 0.00 AC: 0 AN: 3600

South Asian (SAS) AF: 0.00 AC: 0 AN: 2778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.0000187 AC: 1 AN: 53381

Other (OTH) AF: 0.00 AC: 0 AN: 1545

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Wilson-Turner syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	13
DANN	Uncertain	1.0
DEOGEN2	Benign	0.033	T
FATHMM_MKL	Benign	0.36	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.45
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.047
Sift	Benign	0.57	T
Sift4G	Benign	0.51	T
Polyphen		0.0040	B
Vest4		0.063
MutPred		0.38		Gain of sheet (P = 0.039)
MVP		0.61
MPC		0.79
ClinPred		0.037	T
GERP RS		3.9
Varity_R		0.038
gMVP		0.30
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs202068829; hg19: chrX-64738289; COSMIC: COSV56707769; COSMIC: COSV56707769;