NM_019032.6:c.2008C>T

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.2008C>T(p.Arg670*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,611,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

ADAMTSL4
NM_019032.6 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 0.345

Publications

3 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 links:

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

ADAMTSL4-AS2 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 1-150557296-C-T is Pathogenic according to our data. Variant chr1-150557296-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 39557.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.2008C>T	p.Arg670*	stop_gained	Exon 12 of 19	ENST00000271643.9	NP_061905.2	Q6UY14-1Q9UFG7B7ZMJ3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTSL4	ENST00000271643.9 link	c.2008C>T	p.Arg670*	stop_gained	Exon 12 of 19	5	NM_019032.6	ENSP00000271643.4		Q6UY14-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000446

AC:

AN:

246658

AF XY:

0.00000747

show subpopulations

Gnomad AFR exome

AF:

0.0000637

Gnomad AMR exome

AF:

0.0000583

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000549

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000539

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1459794

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726118

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33400

American (AMR)

AF:

0.0000224

AC:

AN:

44562

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26076

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39648

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86026

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52844

Middle Eastern (MID)

AF:

0.000182

AC:

AN:

5498

European-Non Finnish (NFE)

AF:

0.0000207

AC:

AN:

1111446

Other (OTH)

AF:

0.0000663

AC:

AN:

60294

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

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:

0.0000131

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68016

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000179

Hom.:

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ectopia lentis 2, isolated, autosomal recessive

Pathogenic:3

Aug 01, 2010

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Apr 11, 2023

Genome-Nilou Lab

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 04, 2022

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Jul 06, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense 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: 25525159, 27535533, 20564469, 31589614) -

Jan 13, 2025

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.Arg670*) 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 (rs368482584, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with ectopia lentis (PMID: 20564469). ClinVar contains an entry for this variant (Variation ID: 39557). For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic:2

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ADAMTSL4 NM_019032.5 exon 12 p.Arg670* (c.2008C>T): This variant has been reported in the literature in the homozygous state in one individual with isolated ectopia lentis, segregating with disease in one affected family members (Aragon-Martin 2010 PMID:20564469). This variant is also present in 0.006% (1/15690) of African alleles in the Genome Aggregation Database https://gnomad.broadinstitute.org/variant/1-150529772-C-T). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar (Variation ID:39557). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is predicted to cause a stopgain at this codon, resulting in protein truncation or loss of allelic expression through nonsense-mediated mRNA decay. Loss of function variants have been reported in association with disease for this gene (Aragon-Martin 2010 PMID:20564469, Chandra 2012 PMID:22736615, Neuhann 2015 PMID:25975359). In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic. -

Jun 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ectopia lentis et pupillae

Pathogenic:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Benign

0.75

PhyloP100

0.34

Vest4

0.18

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over