rs762602796

Variant names:

• chrX-65514851-G-A
• rs762602796
• NM_031206.7:c.2050C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_031206.7(LAS1L):​c.2050C>T​(p.Arg684Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000184 in 1,084,834 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts 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. R684Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: LAS1L NM_031206.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.39
• 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1581491).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAS1L	NM_031206.7	MANE Select	c.2050C>T	p.Arg684Trp	missense	Exon 13 of 14	NP_112483.1
	LAS1L	NM_001375328.1		c.2047C>T	p.Arg683Trp	missense	Exon 13 of 14	NP_001362257.1
	LAS1L	NM_001170649.2		c.1999C>T	p.Arg667Trp	missense	Exon 12 of 13	NP_001164120.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAS1L	ENST00000374811.8	TSL:1 MANE Select	c.2050C>T	p.Arg684Trp	missense	Exon 13 of 14	ENSP00000363944.3
	LAS1L	ENST00000374807.9	TSL:1	c.1999C>T	p.Arg667Trp	missense	Exon 12 of 13	ENSP00000363940.5
	LAS1L	ENST00000374804.9	TSL:2	c.1873C>T	p.Arg625Trp	missense	Exon 11 of 12	ENSP00000363937.5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.00000623 AC: 1 AN: 160501 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000184 AC: 2 AN: 1084834 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 351994

African (AFR) AF: 0.00 AC: 0 AN: 25975

American (AMR) AF: 0.00 AC: 0 AN: 34037

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18946

East Asian (EAS) AF: 0.00 AC: 0 AN: 29462

South Asian (SAS) AF: 0.00 AC: 0 AN: 52064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40116

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4066

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 834644

Other (OTH) AF: 0.0000220 AC: 1 AN: 45524

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

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	0.18
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.4
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.096
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.11	T
Polyphen		0.52	P
Vest4		0.25
MutPred		0.32		Loss of disorder (P = 0.0087)
MVP		0.59
MPC		0.80
ClinPred		0.96	D
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.52
Mutation Taster		=88/12	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: rs762602796; hg19: chrX-64734731;