rs137948118

Variant names:

• chrX-65528276-C-T
• rs137948118
• NM_031206.7:c.940G>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.940G>A​(p.Val314Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000126 in 1,193,226 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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000062 (0 hom., 2 hem., cov: 24)
  • Exomes 𝑓: 0.0000074 (0 hom. 5 hem.)
• Consequence: LAS1L NM_031206.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.667
• Publications: 1 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=0.016787052).
• BS2: High Hemizygotes in GnomAd4 at 2 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.940G>A	p.Val314Ile	missense	Exon 7 of 14	NP_112483.1	Q9Y4W2-1
	LAS1L	NM_001375328.1		c.940G>A	p.Val314Ile	missense	Exon 7 of 14	NP_001362257.1
	LAS1L	NM_001170649.2		c.940G>A	p.Val314Ile	missense	Exon 7 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.940G>A	p.Val314Ile	missense	Exon 7 of 14	ENSP00000363944.3	Q9Y4W2-1
	LAS1L	ENST00000374807.9	TSL:1	c.940G>A	p.Val314Ile	missense	Exon 7 of 13	ENSP00000363940.5	Q9Y4W2-2
	LAS1L	ENST00000867035.1		c.940G>A	p.Val314Ile	missense	Exon 7 of 14	ENSP00000537094.1

Frequencies

GnomAD3 genomes AF: 0.0000622 AC: 7 AN: 112571 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000194

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000598 AC: 1 AN: 167294 AF XY: 0.0000184

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000137

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000740 AC: 8 AN: 1080601 Hom.: 0 Cov.: 27 AF XY: 0.0000144 AC XY: 5 AN XY: 348363

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000115 AC: 3 AN: 26022

American (AMR) AF: 0.00 AC: 0 AN: 34591

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19166

East Asian (EAS) AF: 0.00 AC: 0 AN: 29939

South Asian (SAS) AF: 0.00 AC: 0 AN: 52725

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40144

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3892

European-Non Finnish (NFE) AF: 0.00000362 AC: 3 AN: 828610

Other (OTH) AF: 0.0000439 AC: 2 AN: 45512

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0232839), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000622 AC: 7 AN: 112625 Hom.: 0 Cov.: 24 AF XY: 0.0000575 AC XY: 2 AN XY: 34787

African (AFR) AF: 0.000193 AC: 6 AN: 31030

American (AMR) AF: 0.00 AC: 0 AN: 10689

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3578

South Asian (SAS) AF: 0.00 AC: 0 AN: 2758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6227

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53256

Other (OTH) AF: 0.00 AC: 0 AN: 1536

Alfa AF: 0.000130 Hom.: 1

Bravo AF: 0.0000416

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

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	0.060
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.014	T
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.7	N
PhyloP100		0.67
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.48	N
REVEL	Benign	0.065
Sift	Benign	1.0	T
Sift4G	Benign	0.95	T
Polyphen		0.0010	B
Vest4		0.058
MVP		0.10
MPC		0.51
ClinPred		0.099	T
GERP RS		0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.026
gMVP		0.16
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs137948118; hg19: chrX-64748156;