rs148565559

chr16-88837689-A-Cchr16-88837689-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_000512.5(GALNS):c.499T>G(p.Phe167Val) variant causes a missense change. The variant allele was found at a frequency of 0.00156 in 1,614,082 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (4 hom.)
• Consequence: GALNS NM_000512.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5
• Conservation: PhyloP100: 6.99

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 Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000512.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.13681221).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALNS	NM_000512.5	c.499T>G	p.Phe167Val	missense_variant	5/14	ENST00000268695.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALNS	ENST00000268695.10	c.499T>G	p.Phe167Val	missense_variant	5/14	1	NM_000512.5	P1

Frequencies

GnomAD3 genomes AF: 0.00117 AC: 178 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00219

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00103 AC: 260 AN: 251410 Hom.: 1 AF XY: 0.00100 AC XY: 136 AN XY: 135886

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00174

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00160 AC: 2346 AN: 1461798 Hom.: 4 Cov.: 32 AF XY: 0.00156 AC XY: 1132 AN XY: 727206

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000760

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000417

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.00196

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00117 AC: 178 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.00109 AC XY: 81 AN XY: 74466

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00219

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00151 Hom.: 0

Bravo AF: 0.00118

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.000898 AC: 109

EpiCase AF: 0.00153

EpiControl AF: 0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mucopolysaccharidosis, MPS-IV-A Uncertain:4

Uncertain significance, criteria provided, single submitter	curation	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	Feb 01, 2021	In vitro functional studies supportive of a damaging effect on the gene product (low in vitro enzymatic activity; PS3_supporting); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting) -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The GALNS c.499T>G (p.Phe167Val) missense variant has been reported in two studies in which it was identified in a compound heterozygous state in two patients (siblings) who were described as having an attenuated clinical phenotype of mucopolysaccharidosis, type IVa (Tomatsu et al. 2005; Montaño et al. 2007). The variant was found in two of 383 control alleles and is reported at a frequency of 0.00163 in the European American population of the Exome Sequencing Project. Functional studies using stable expression in CHO-K1 cell lines showed that the p.Phe167Val variant reduced enzyme activity (7.5% of wild type) and substrate affinity when compared to wild type GALNS (Montaño et al. 2007). In silico analysis revealed that the Phe167 residue is located near the active site on the surface of the GALNS protein and is predicted to change the secondary structure of the protein and affect substrate recognition and binding (Rivera-Colón et al. 2012; Olarte-Avellaneda et al. 2014; Tamarozzi et al. 2014). Based on the limited evidence, the p.Phe167Val variant is classified as a variant of unknown significance, but suspicious for pathogenicity for mucopolysaccharidosis, type IV. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 30, 2022	This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 167 of the GALNS protein (p.Phe167Val). This variant is present in population databases (rs148565559, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with mucopolysaccharidosis IVA (PMID: 17876718). ClinVar contains an entry for this variant (Variation ID: 321204). 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. Experimental studies have shown that this missense change affects GALNS function (PMID: 17876718). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Dec 15, 2021

PP3, PM2, PM3_supporting, PS3 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jan 16, 2024

Variant summary: GALNS c.499T>G (p.Phe167Val) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 1614082 control chromosomes, predominantly at a frequency of 0.002 within the Non-Finnish European subpopulation in the gnomAD database, including 3 homozygotes. The Non-Finnish European subpopulation frequency is similar to the estimated frequency for a pathogenic variant in GALNS causing Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (0.002 vs 0.002) suggesting a possible benign role for this variant. c.499T>G has been reported in the literature in individuals affected with an attenuated form of Mucopolysaccharidosis Type IVA. Two of these cases were reported with a second allele with uncertain significance (Morquio Syndrome A, e.g. Tomatsu_2005, Montano_2007) while the third case was reported to have mild features of the disease with a strong loss of function variant (Hiatt_2023). At least one publication reports experimental evidence evaluating an impact on protein function, indicating that the variant results in reduced activity and reduced affinity for substrate (e.g. Montano_2007). The following publications have been ascertained in the context of this evaluation (PMID: 34828358, 17876718, 25287660, 22940367, 31732130, 25501214, 16287098, 36586412). These data suggest that the pathogenicity of the variant may be genotype dependent. ClinVar contains an entry for this variant (Variation ID: 321204). Based on the evidence outlined above, the variant was classified as VUS - possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Benign	0.98	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Pathogenic	0.85
Sift	Benign	0.26	T;T
Sift4G	Benign	0.48	T;.
Polyphen		0.91	P;.
Vest4		0.59
MVP		1.0
MPC		0.36
ClinPred		0.033	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.81
gMVP		0.93

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: rs148565559; hg19: chr16-88904097;