rs144067930

chr16-88835261-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP5

The NM_000512.5(GALNS):c.850T>G(p.Phe284Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000333 in 1,610,180 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F284C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: GALNS NM_000512.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 9.09

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 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 chr16-88835260-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2840507.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 16-88835261-A-C is Pathogenic according to our data. Variant chr16-88835261-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 321200.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALNS	NM_000512.5	c.850T>G	p.Phe284Val	missense_variant	8/14	ENST00000268695.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALNS	ENST00000268695.10	c.850T>G	p.Phe284Val	missense_variant	8/14	1	NM_000512.5	P1

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152176 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000217 AC: 53 AN: 244338 Hom.: 0 AF XY: 0.000272 AC XY: 36 AN XY: 132198

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000118

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000275

Gnomad SAS exome AF: 0.0000677

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000380

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000346 AC: 504 AN: 1457886 Hom.: 0 Cov.: 32 AF XY: 0.000326 AC XY: 236 AN XY: 724812

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000904

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.000352

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000395

Gnomad4 OTH exome AF: 0.000332

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152294 Hom.: 1 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74454

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000379 Hom.: 0

Bravo AF: 0.000223

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000231 AC: 28

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mucopolysaccharidosis, MPS-IV-A Pathogenic:3 Uncertain:1

Uncertain significance, criteria provided, single submitter	curation	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_supporting); the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_supporting); very low frequency in gnomAD v2.1.1 (PM2_moderate) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The GALNS c.850T>G (p.Phe284Val) missense variant has been reported in three studies in which it is found in a total of three patients with mucopolysaccharidosis type IV, including in one in a homozygous state, in one in a compound heterozygous state with a deletion on the second allele, and in one in a heterozygous state (Yamada et al. 1998; Dung et al. 2013; Morrone et al. 2014). The p.Phe284Val variant was absent from 200 control chromosomes (Dung et al. 2013), and is reported at a frequency of 0.0008 in the total population of the 1000 Genomes Project. The Phe284 residue is highly conserved and is located in a hydrophobic core of the protein (Dung et al. 2013; Olarte-Avellaneda et al. 2014). Enzyme activity in the individual who was compound hetreozygous for the variant was demonstrated to be only 4% of wild type (Morrone et al. 2014). Based on the evidence, the p.Phe284Val variant is classified as likely pathogenic for mucopolysaccharidosis, type IV. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 284 of the GALNS protein (p.Phe284Val). This variant is present in population databases (rs144067930, gnomAD 0.03%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with mucopolysaccharidosis IV (PMID: 23876334, 30980944). ClinVar contains an entry for this variant (Variation ID: 321200). 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%. For these reasons, this variant has been classified as Pathogenic. -

Morquio syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 31, 2023	Variant summary: GALNS c.850T>G (p.Phe284Val) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 244338 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GALNS causing Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (0.00022 vs 0.002), allowing no conclusion about variant significance. c.850T>G has been reported in the literature in individuals affected with Mucopolysaccharidosis (examples: Yamada_1998, Dung_2013, and Tuysuz_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=1), likely pathogenic (n=3) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 09, 2016	The p.Phe284Val variant in GALNS has been reported in four patients with mucopol ysaccharidosis type IVa (one compound heterozygote and two homozygotes) (Yamada 1998, Morrone 2014, Dung 2013). This variant has also been identified in 0.04% ( 28/75778) of chromosomes by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs144067930). Although this variant has been seen in t he general population, its frequency is low enough to be consistent with a reces sive carrier frequency. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summa ry, although additional studies are required to fully establish its clinical sig nificance, the p.Phe284Val variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Benign	19
Dann	Benign	0.46
DEOGEN2	Uncertain	0.70	D
Eigen	Benign	-0.10
Eigen_PC	Benign	0.017
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Uncertain	0.021	D
MutationAssessor	Benign	-1.2	N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.74
Sift	Benign	0.91	T
Sift4G	Benign	0.58	T
Polyphen		0.30	B
Vest4		0.93
MVP		0.99
MPC		0.19
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.88

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: rs144067930; hg19: chr16-88901669;