rs750436732

Variant names:

• chrX-65529678-C-A
• rs750436732
• NM_031206.7:c.715G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_031206.7(LAS1L):​c.715G>T​(p.Asp239Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000231 in 1,209,967 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 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. D239G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000024 (0 hom. 7 hem.)
• Consequence: LAS1L NM_031206.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.0210
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0836049).
• BS2: High Hemizygotes in GnomAdExome4 at 7 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.715G>T	p.Asp239Tyr	missense	Exon 5 of 14	NP_112483.1	Q9Y4W2-1
	LAS1L	NM_001375328.1		c.715G>T	p.Asp239Tyr	missense	Exon 5 of 14	NP_001362257.1
	LAS1L	NM_001170649.2		c.715G>T	p.Asp239Tyr	missense	Exon 5 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.715G>T	p.Asp239Tyr	missense	Exon 5 of 14	ENSP00000363944.3	Q9Y4W2-1
	LAS1L	ENST00000374807.9	TSL:1	c.715G>T	p.Asp239Tyr	missense	Exon 5 of 13	ENSP00000363940.5	Q9Y4W2-2
	LAS1L	ENST00000867035.1		c.715G>T	p.Asp239Tyr	missense	Exon 5 of 14	ENSP00000537094.1

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111835 Hom.: 0 Cov.: 23

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: 0.0000376

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000872 AC: 16 AN: 183502 AF XY: 0.0000883

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000547

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000237 AC: 26 AN: 1098132 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 7 AN XY: 363486

African (AFR) AF: 0.00 AC: 0 AN: 26402

American (AMR) AF: 0.000682 AC: 24 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54143

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40523

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 842035

Other (OTH) AF: 0.00 AC: 0 AN: 46094

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111835 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33995

African (AFR) AF: 0.00 AC: 0 AN: 30738

American (AMR) AF: 0.00 AC: 0 AN: 10516

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3581

South Asian (SAS) AF: 0.00 AC: 0 AN: 2684

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6055

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53184

Other (OTH) AF: 0.00 AC: 0 AN: 1505

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.0000494 AC: 6

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)
-	1	-	Wilson-Turner syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	15
DANN	Benign	0.71
DEOGEN2	Benign	0.034	T
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.021
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.051
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.87	P
Vest4		0.25
MutPred		0.24		Gain of phosphorylation at D239 (P = 0.0045)
MVP		0.26
MPC		1.7
ClinPred		0.12	T
GERP RS		2.5
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.10
gMVP		0.29
Mutation Taster		=95/5	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: rs750436732; hg19: chrX-64749558; COSMIC: COSV104612622;