rs745356580

Variant names:

• chrX-65529646-G-A
• rs745356580
• NM_031206.7:c.747C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The ENST00000374811.8(LAS1L):​c.747C>T​(p.Ser249Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,209,516 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000012 (0 hom. 3 hem.)
• Consequence: LAS1L ENST00000374811.8 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.755
• 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant X-65529646-G-A is Benign according to our data. Variant chrX-65529646-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 533411.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.755 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome4 at 3 Unknown,XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000374811.8. 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.747C>T	p.Ser249Ser	synonymous	Exon 5 of 14	NP_112483.1
	LAS1L	NM_001375328.1		c.747C>T	p.Ser249Ser	synonymous	Exon 5 of 14	NP_001362257.1
	LAS1L	NM_001170649.2		c.747C>T	p.Ser249Ser	synonymous	Exon 5 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.747C>T	p.Ser249Ser	synonymous	Exon 5 of 14	ENSP00000363944.3
	LAS1L	ENST00000374807.9	TSL:1	c.747C>T	p.Ser249Ser	synonymous	Exon 5 of 13	ENSP00000363940.5
	LAS1L	ENST00000374804.9	TSL:2	c.621C>T	p.Ser207Ser	synonymous	Exon 4 of 12	ENSP00000363937.5

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111493 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000191

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000491 AC: 9 AN: 183389 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000488

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000118 AC: 13 AN: 1098023 Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 3 AN XY: 363379

African (AFR) AF: 0.00 AC: 0 AN: 26401

American (AMR) AF: 0.000114 AC: 4 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19383

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

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40491

Middle Eastern (MID) AF: 0.000484 AC: 2 AN: 4134

European-Non Finnish (NFE) AF: 0.00000594 AC: 5 AN: 841974

Other (OTH) AF: 0.0000217 AC: 1 AN: 46085

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111493 Hom.: 0 Cov.: 23 AF XY: 0.0000297 AC XY: 1 AN XY: 33713

African (AFR) AF: 0.00 AC: 0 AN: 30661

American (AMR) AF: 0.000191 AC: 2 AN: 10474

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3561

South Asian (SAS) AF: 0.00 AC: 0 AN: 2660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5997

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53084

Other (OTH) AF: 0.00 AC: 0 AN: 1498

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	LAS1L-related disorder (1)
-	-	1	Wilson-Turner syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.5
DANN	Benign	0.47
PhyloP100		0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
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: rs745356580; hg19: chrX-64749526; COSMIC: COSV56707814;