rs794726887

Positions:

• chr16-88856766-TGAGCAG-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM4 PP5

The NM_000512.5(GALNS):​c.106_111delCTGCTC​(p.Leu36_Leu37del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.00000273 in 1,466,912 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000069 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: GALNS NM_000512.5 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 4.36

Genes affected

GALNS (HGNC:4122): (galactosamine (N-acetyl)-6-sulfatase) This gene encodes N-acetylgalactosamine-6-sulfatase which is a lysosomal exohydrolase required for the degradation of the glycosaminoglycans, keratan sulfate, and chondroitin 6-sulfate. Sequence alterations including point, missense and nonsense mutations, as well as those that affect splicing, result in a deficiency of this enzyme. Deficiencies of this enzyme lead to Morquio A syndrome, a lysosomal storage disorder. [provided by RefSeq, Jul 2008]

TRAPPC2L (HGNC:30887): (trafficking protein particle complex subunit 2L) This gene encodes a protein that interacts with the tethering factor trafficking protein particle (TRAPP complex). TRAPP complexes mediate the contact between vescicles and target membranes, and thus, are involved in vescicle-mediated transport of proteins and lipids. The encoded protein is related to the X-linked trafficking protein particle complex 2. A related pseudogene is located on the X chromosome. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000512.5.
• PP5: Variant 16-88856766-TGAGCAG-T is Pathogenic according to our data. Variant chr16-88856766-TGAGCAG-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193104.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALNS	NM_000512.5	c.106_111delCTGCTC	p.Leu36_Leu37del	conservative_inframe_deletion	1/14	ENST00000268695.10	NP_000503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALNS	ENST00000268695.10	c.106_111delCTGCTC	p.Leu36_Leu37del	conservative_inframe_deletion	1/14	1	NM_000512.5	ENSP00000268695.5

Frequencies

GnomAD3 genomes AF: 0.00000686 AC: 1 AN: 145794 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000209

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

GnomAD4 exome AF: 0.00000227 AC: 3 AN: 1321118 Hom.: 0 AF XY: 0.00000307 AC XY: 2 AN XY: 652342

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000658

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.64e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000686 AC: 1 AN: 145794 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 71020

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000209

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mucopolysaccharidosis, MPS-IV-A Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	research	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	Feb 01, 2021	The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_moderate); absent from gnomAD v2.1.1 (PM2_moderate); protein length changes as a result of in-frame deletions/insertions in a nonrepeat region (PM4_supporting) -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 05, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 14, 2023	This variant has been observed in individuals with mucopolysaccharidosis type IVA (PMID: 11524742, 31200731). This variant is not present in population databases (gnomAD no frequency). This variant, c.106_111del, results in the deletion of 2 amino acid(s) of the GALNS protein (p.Leu36_Leu37del), but otherwise preserves the integrity of the reading frame. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the GALNS protein in which other variant(s) (p.Leu36Arg) have been determined to be pathogenic (PMID: 24726177, 25252036; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. -

Morquio syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 09, 2023

Variant summary: GALNS c.106_111delCTGCTC (p.Leu36_Leu37del) results in an in-frame deletion that is predicted to remove two amino acids from the encoded protein. The variant was absent in 149554 control chromosomes. c.106_111delCTGCTC has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A)(example, Yang_2001, Hu_2018, Leong_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36077388, 29095814, 31200731, 20574428, 11524742, 35212421). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 10, 2014

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs794726887; hg19: chr16-88923174;