rs1308500116

chr16-88837722-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000512.5(GALNS):c.466T>C(p.Phe156Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F156C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: GALNS NM_000512.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.98

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000512.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-88837721-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 623188.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=1, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 16-88837722-A-G is Pathogenic according to our data. Variant chr16-88837722-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 528321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALNS	NM_000512.5	c.466T>C	p.Phe156Leu	missense_variant	5/14	ENST00000268695.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALNS	ENST00000268695.10	c.466T>C	p.Phe156Leu	missense_variant	5/14	1	NM_000512.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251344 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135872

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461740 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727170

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-IV-A Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 13, 2022	- -
Likely pathogenic, criteria provided, single submitter	research	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	Feb 01, 2021	In vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; PS3_moderate); the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_strong); very low frequency in gnomAD v2.1.1 (PM2_moderate); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 156 of the GALNS protein (p.Phe156Leu). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individuals with mucopolysaccharidosis IVa (PMID: 24726177; Invitae). ClinVar contains an entry for this variant (Variation ID: 528321). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GALNS protein function with a positive predictive value of 95%. This variant disrupts the p.Phe156 amino acid residue in GALNS. Other variant(s) that disrupt this residue have been observed in individuals with GALNS-related conditions (PMID: 9298823, 9521421), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Morquio syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Mar 23, 2022

Variant summary: GALNS c.466T>C (p.Phe156Leu) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251344 control chromosomes (gnomAD). c.466T>C has been reported in the literature in at least two homozygous individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (Examples: Cozma_2015 and Morrone_2014). Cozma_2015 demonstrated that GALINS activity in leucocytes from the homozygous individual was <1 (Normal range 107-198 nmol MU/mg protein). These data indicate that the variant is very likely to be associated with disease. Additionally, other missense variants in the same residue (F156S and F156C) have been reported in the Human Gene Mutation Database in association with Mucopolysaccharidosis Type IVA (PMID: 9521421, 9298823), supporting the functional importance of this residue of the protein. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 07, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24120057, 24726177, 26147980) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.4	D;D
REVEL	Pathogenic	1.0
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.99
MutPred		0.91		Gain of sheet (P = 0.0477);.;
MVP		1.0
MPC		0.54
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.98

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: rs1308500116; hg19: chr16-88904130; COSMIC: COSV51937428; COSMIC: COSV51937428;