1-150558029-TG-TGG

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_019032.6(ADAMTSL4):c.2270dupG(p.Gly758TrpfsTer59) variant causes a frameshift change. The variant allele was found at a frequency of 0.00013 in 1,611,698 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G757G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

ADAMTSL4
NM_019032.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 3.92

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

ectopia lentis 2, isolated, autosomal recessive
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics
ectopia lentis et pupillae
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
isolated ectopia lentis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ADAMTSL4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

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

PP5

Variant 1-150558029-T-TG is Pathogenic according to our data. Variant chr1-150558029-T-TG is described in ClinVar as Pathogenic. ClinVar VariationId is 39559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTSL4	NM_019032.6 link	c.2270dupG	p.Gly758TrpfsTer59	frameshift_variant	Exon 14 of 19	ENST00000271643.9	NP_061905.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTSL4	ENST00000271643.9 link	c.2270dupG	p.Gly758TrpfsTer59	frameshift_variant	Exon 14 of 19	5	NM_019032.6	ENSP00000271643.4

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

151650

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000267

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000658

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:

0.000103

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.000488

AC:

119

AN:

243982

AF XY:

0.000262

show subpopulations

Gnomad AFR exome

AF:

0.000872

Gnomad AMR exome

AF:

0.0000874

Gnomad ASJ exome

AF:

0.000510

Gnomad EAS exome

AF:

0.0000550

Gnomad FIN exome

AF:

0.0000475

Gnomad NFE exome

AF:

0.000704

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.000129

AC:

188

AN:

1459930

Hom.:

Cov.:

AF XY:

0.000138

AC XY:

100

AN XY:

726216

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33470

American (AMR)

AF:

0.0000447

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39690

South Asian (SAS)

AF:

0.000487

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.000537

AC:

AN:

52094

Middle Eastern (MID)

AF:

0.000348

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.0000945

AC:

105

AN:

1111536

Other (OTH)

AF:

0.0000829

AC:

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.428

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000138

AC:

AN:

151768

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74160

show subpopulations

African (AFR)

AF:

0.000266

AC:

AN:

41368

American (AMR)

AF:

0.0000657

AC:

AN:

15210

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5144

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10560

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

67898

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000260

Hom.:

Bravo

AF:

0.000106

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ectopia lentis 2, isolated, autosomal recessive

Pathogenic:2

Jun 24, 2022

Genetics and Molecular Pathology, SA Pathology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ADAMTSL4 c.2270dup variant is classified as a PATHOGENIC VARIANT (PVS1, PS4, PP5) This variant is a 1-base pair duplication in exon 14/19 of the ADAMTSL4 gene which results in a frameshift starting at codon Glycine 758, changing this amino acid to a Tryptophan residue, and creating a premature Stop codon at 59 amino acids downstream (PVS1). This is a recurrent 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: 22736615, 23426735, 28642162, 20564469). The variant is in dbSNP (rs747160538) and has been reported in population databases consistent with recessive carrier frequency (gnomAD: 21/151650, 0 homozygote). The variant has been reported in ClinVar (Variation ID: 39559) and HGMD (Accession No: CI127501) as pathogenic/disease causing (PS4). Patient's clinical phenotype is highly specific for ADAMTSL4 (PP5).

Apr 11, 2023

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Pathogenic:2

Nov 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Gly758Trpfs*59) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with ectopia lentis (PMID: 22736615). ClinVar contains an entry for this variant (Variation ID: 39559). For these reasons, this variant has been classified as Pathogenic.

Apr 18, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified with a second ADAMTSL4 variant (phase unknown) in unrelated patients with isolated ectopia lentis et pupillae in published literature (Chandra et al., 2012; Sharifi et al., 2013); 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; Not observed in large population cohorts (gnomAD); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#39559); This variant is associated with the following publications: (PMID: 22736615, 23426735, 35218299)

Ectopia lentis et pupillae

Pathogenic:2

Jul 24, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Apr 11, 2023

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Pathogenic:1

Jun 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.9

Mutation Taster

=2/198

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over