1-150558029-TG-TGG

Position:

• chr1-150558029-TG-TGG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_019032.6(ADAMTSL4):​c.2270dupG​(p.Gly758fs) 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 3.92

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-150558029-T-TG is Pathogenic according to our data. Variant chr1-150558029-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 39559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTSL4	NM_019032.6	c.2270dupG	p.Gly758fs	frameshift_variant	14/19	ENST00000271643.9	NP_061905.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTSL4	ENST00000271643.9	c.2270dupG	p.Gly758fs	frameshift_variant	14/19	5	NM_019032.6	ENSP00000271643.4

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 151650 Hom.: 0 Cov.: 33

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

GnomAD4 exome AF: 0.000129 AC: 188 AN: 1459930 Hom.: 1 Cov.: 33 AF XY: 0.000138 AC XY: 100 AN XY: 726216

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000487

Gnomad4 FIN exome AF: 0.000537

Gnomad4 NFE exome AF: 0.0000945

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome AF: 0.000138 AC: 21 AN: 151768 Hom.: 0 Cov.: 33 AF XY: 0.000135 AC XY: 10 AN XY: 74160

Gnomad4 AFR AF: 0.000266

Gnomad4 AMR AF: 0.0000657

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000948

Bravo AF: 0.000106

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ectopia lentis 2, isolated, autosomal recessive Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jun 24, 2022	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 18, 2022	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

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 24, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Ectopia lentis et pupillae;C3541474:Ectopia lentis 2, isolated, autosomal recessive Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jun 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs747160538; hg19: chr1-150530505;