rs199473693

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_019032.6(ADAMTSL4):c.767_786del(p.Gln256ProfsTer38) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,613,744 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0018 ( 2 hom. )

Consequence

ADAMTSL4
NM_019032.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:20O:2

Conservation

PhyloP100: 0.968

Variant links:

Genes affected

ADAMTSL4 (HGNC:19706): (ADAMTS like 4) This gene is a member of ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs)-like gene family and encodes a protein with seven thrombospondin type 1 repeats. The thrombospondin type 1 repeat domain is found in many proteins with diverse biological functions including cellular adhesion, angiogenesis, and patterning of the developing nervous system. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Sep 2014]

ADAMTSL4 links:

ADAMTSL4-AS2 (HGNC:40895): (ADAMTSL4 antisense RNA 2)

ADAMTSL4-AS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 1-150553749-CCAGAGCCCAGGCCTCTGGCA-C is Pathogenic according to our data. Variant chr1-150553749-CCAGAGCCCAGGCCTCTGGCA-C is described in ClinVar as [Pathogenic]. Clinvar id is 39555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-150553749-CCAGAGCCCAGGCCTCTGGCA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTSL4	NM_019032.6 linkuse as main transcript	c.767_786del	p.Gln256ProfsTer38	frameshift_variant	6/19	ENST00000271643.9
ADAMTSL4-AS2	XR_001738229.2 linkuse as main transcript	n.210+2185_210+2204del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTSL4	ENST00000271643.9 linkuse as main transcript	c.767_786del	p.Gln256ProfsTer38	frameshift_variant	6/19	5	NM_019032.6	P1	Q6UY14-1
ADAMTSL4-AS2	ENST00000442435.3 linkuse as main transcript	n.476+766_476+785del		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00118

AC:

180

AN:

151926

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000194

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00231

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.00121

AC:

303

AN:

250950

Hom.:

AF XY:

0.00116

AC XY:

157

AN XY:

135628

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.000462

Gnomad NFE exome

AF:

0.00240

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00182

AC:

2656

AN:

1461700

Hom.:

AF XY:

0.00172

AC XY:

1250

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.000880

Gnomad4 NFE exome

AF:

0.00226

Gnomad4 OTH exome

AF:

0.00121

GnomAD4 genome

AF:

0.00118

AC:

180

AN:

152044

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000660

Gnomad4 NFE

AF:

0.00231

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.00174

Hom.:

EpiCase

AF:

0.00185

EpiControl

AF:

0.00178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ectopia lentis 2, isolated, autosomal recessive

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 24, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 09, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Aug 28, 2019	A homozygous frameshift deletion variant was identified, NM_019032.5(ADAMTSL4):c.767_786del in exon 6 of 19 of the ADAMTSL4 gene. This deletion is predicted to cause a frameshift starting at position 256, introducing a stop codon 37 residues downstream, NP_061905.2(ADAMTSL4):p.(Gln256Profs*38). The variant is predicted to result in a loss of normal protein function through nonsense-mediated decay (NMD). The variant is present in the gnomAD population database at a frequency of 0.12% (344 heterozygotes; 0 homozygotes). The variant has previously been reported as pathogenic in multiple patients with ectopia lentis (ClinVar, Aragon-Martin, J. et al. (2010), Neuhann, T. et al. (2011), Neuhann, T. et al. (2015)). Based on information available at the time of curation, this variant has been classified as PATHOGENIC. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 26, 2017	The ADAMTSL4 c.767_786delAGGCCTCTGGCACAGAGCCC (p.Gln256ProfsTer38) variant results in a frameshift, and is predicted to result in premature termination of the protein. The p.Gln256ProfsTer38 variant has been reported in at least six studies in which it is found in a total of 39 individuals with ectopia lentis from at least 12 families, including in 33 individuals in a homozygous state (of whom at least 11 are related), five individuals in a compound heterozygous state and in one individual in a heterozygous state (Aragon-Martin et al. 2010; Christensen et al. 2010; Neuhann et al. 2011; Chandra et al. 2012; Chandra et al. 2013; Neuhann et al. 2015). The variant has also been found in a heterozygous state in eight unaffected family members. The p.Gln256ProfsTer38 variant was observed in a heterozygous state in five of 550 control individuals (Christensen et al. 2010; Neuhann et al. 2011) and is reported at a frequency of 0.002423 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence and the potential impact of frameshift variants, the p.Gln256ProfsTer38 variant is classified as pathogenic for ectopia lentis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jun 24, 2022	The ADAMTSL4 c.767_786del variant is classified as a PATHOGENIC VARIANT (PVS1, PS4, PP5) This variant is a 20-base pair deletion in exon 6 of the ADAMTSL4 gene which results in a frameshift starting with codon Glutamine 256, changes this amino acid to a Proline residue, and creates a premature Stop codon at position 38 of the new reading frame, denoted p.Q256PfsX38. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay (PVS1). This variant is common pathogenic variant in the ADAMTSL4 gene, and has been previously reported in many individuals with Ectopia lentis in both the homozygous or compound heterozygous state (PMID: 21051722, 22871183, 28642162, 20564469) (PS4). The variant is in dbSNP (rs199473693) and has been reported in population databases (gnomAD: 344/282186, 0 homozygote). The variant has been reported in ClinVar (Variation ID: 39555) and HGMD (Accession No: CD104803) as Pathogenic (PP5). -

not provided

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 11, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ADAMTSL4: PM3:Very Strong, PVS1, PP1:Strong, PM2:Supporting, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	This sequence change creates a premature translational stop signal (p.Gln256Profs*38) in the ADAMTSL4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ADAMTSL4 are known to be pathogenic (PMID: 20564469, 28642162). This variant is present in population databases (rs587691401, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with ectopia lentis (PMID: 2056446, 21051722, 22736615, 22871183, 25975359). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39555). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Dec 07, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2022	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20564469, 22871183, 21051722, 27848971, 23426735, 20702823, 22736615, 28642162, 28394649, 31980526, 31282960, 34426522, 31589614, 33726816) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Feb 01, 2022	PM3, PVS1, PP3, PP5, PS4, PP1 -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 15, 2019	- -

Ectopia lentis et pupillae

Pathogenic:2Other:2

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 24, 2012	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Pathogenic and reported on 06-26-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Ectopia lentis et pupillae;C3541474:Ectopia lentis 2, isolated, autosomal recessive

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Jul 21, 2022	This variant has been reported in the literature in the homozygous and compound heterozygous states in numerous individuals with ectopia lentis, segregating with disease in at least 6 affected family members (Selected publications: Aragon-Martin 2010 PMID: 20564469; Christensen 2010 PMID: 20702823; Neuhann 2011 PMID: 21051722; Chandra 2012 PMID: 22736615). This variant is present in 0.2% (307/128702) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/1-150526225-CCAGAGCCCAGGCCTCTGGCA-C?dataset=gnomad_r2_1). Of note, this variant has been described as or suggested to be a founder mutation in multiple European populations (Christensen 2010 PMID: 20702823; Neuhann 2011 PMID: 21051722; Overwater 2017 PMID: 28642162). This variant is present in ClinVar, with several laboratories classifying it as pathogenic (Variation ID: 39555). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant creates a premature stop codon 38 amino acids downstream from this location which results in an absent or abnormal protein; loss of function variants are a known mechanism of disease for this gene (Rødahl 2020 PMID: 22338190). In summary, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 29, 2021	- -

Ectopia lentis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 14, 2014

The p.Gln256ProfsX38 variant in ADAMTSL4 has been reported in >20 compound heter ozygous or homozygous individuals with ectopia lentis and was found to segregate with disease in 6 affected relatives from 5 families (Aragon -Martin 2010, Chri stensen 2010, Neuhann 2011, Chandra 2013, Overwater 2017). The p.Gln256ProfsX38 variant has been identified in 0.24% (306/126278) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP r s199473693). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Thi s variant is predicted to cause a frameshift, which alters the protein?s amino a cid sequence beginning at position 256 and leads to a premature termination codo n 38 amino acids downstream. This alteration has been shown to lead to a truncat ed mRNA (Christensen 2010) and is predicted to lead to a truncated or absent pro tein. Complete loss-of-function of the ADAMTSL4 gene is an established disease m echanism in individuals with ectopia lentis. In summary, this variant meets our criteria to be classified as pathogenic for ectopia lentis in an autosomal reces sive manner based upon segregation studies and the impact of the variant. ACMG/A MP Criteria applied: PVS1; PM3_Very strong; PP1_Moderate. -

Craniosynostosis with ectopia lentis

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Cunningham Lab, Seattle Childrens Research Institute

Nov 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over