rs867562406

Variant names:

• chrX-65524575-G-C
• rs867562406
• NM_031206.7:c.1082C>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_031206.7(LAS1L):​c.1082C>G​(p.Pro361Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000495 in 525,110 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P361P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.000058 (0 hom. 12 hem.)
• Consequence: LAS1L NM_031206.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.928
• 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: 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06995916).
• BP6: Variant X-65524575-G-C is Benign according to our data. Variant chrX-65524575-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 464820.
• BS2: High Hemizygotes in GnomAdExome4 at 12 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAS1L	NM_031206.7	MANE Select	c.1082C>G	p.Pro361Arg	missense	Exon 9 of 14	NP_112483.1
	LAS1L	NM_001375328.1		c.1082C>G	p.Pro361Arg	missense	Exon 9 of 14	NP_001362257.1
	LAS1L	NM_001375329.1		c.1082C>G	p.Pro361Arg	missense	Exon 9 of 12	NP_001362258.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAS1L	ENST00000374811.8	TSL:1 MANE Select	c.1082C>G	p.Pro361Arg	missense	Exon 9 of 14	ENSP00000363944.3
	LAS1L	ENST00000374807.9	TSL:1	c.1043-313C>G		intron	N/A	ENSP00000363940.5
	LAS1L	ENST00000677087.1		c.734C>G	p.Pro245Arg	missense	Exon 10 of 15	ENSP00000503907.1

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111689 Hom.: 0 Cov.: 22

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: 0.00847

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000581 AC: 24 AN: 413367 Hom.: 0 Cov.: 0 AF XY: 0.0000788 AC XY: 12 AN XY: 152349

African (AFR) AF: 0.00 AC: 0 AN: 12489

American (AMR) AF: 0.00 AC: 0 AN: 26989

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14643

East Asian (EAS) AF: 0.00 AC: 0 AN: 24114

South Asian (SAS) AF: 0.00 AC: 0 AN: 37788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37491

Middle Eastern (MID) AF: 0.00469 AC: 14 AN: 2984

European-Non Finnish (NFE) AF: 0.0000342 AC: 8 AN: 233605

Other (OTH) AF: 0.0000860 AC: 2 AN: 23264

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111743 Hom.: 0 Cov.: 22 AF XY: 0.0000295 AC XY: 1 AN XY: 33947

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

African (AFR) AF: 0.00 AC: 0 AN: 30773

American (AMR) AF: 0.00 AC: 0 AN: 10611

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3529

South Asian (SAS) AF: 0.00 AC: 0 AN: 2645

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6042

Middle Eastern (MID) AF: 0.00930 AC: 2 AN: 215

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53071

Other (OTH) AF: 0.00 AC: 0 AN: 1526

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.048	T
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.93
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.047
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.0020	B
Vest4		0.19
MutPred		0.16		Gain of phosphorylation at S363 (P = 0.0779)
MVP		0.14
MPC		0.93
ClinPred		0.23	T
GERP RS		0.70
Varity_R		0.26
gMVP		0.42
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: 39

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs867562406; hg19: chrX-64744455;