rs118204438

chr16-88841077-T-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_Very_Strong

The NM_000512.5(GALNS):c.337A>T(p.Ile113Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,612,652 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I113T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: GALNS NM_000512.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 2.31

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 14 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 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 chr16-88841076-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1515475.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 16-88841077-T-A is Pathogenic according to our data. Variant chr16-88841077-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88841077-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALNS	NM_000512.5	c.337A>T	p.Ile113Phe	missense_variant	4/14	ENST00000268695.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALNS	ENST00000268695.10	c.337A>T	p.Ile113Phe	missense_variant	4/14	1	NM_000512.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000790 AC: 12 AN: 151808 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000399 AC: 10 AN: 250884 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135850

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000706

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000151 AC: 220 AN: 1460844 Hom.: 0 Cov.: 31 AF XY: 0.000157 AC XY: 114 AN XY: 726742

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.000184

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.0000790 AC: 12 AN: 151808 Hom.: 0 Cov.: 33 AF XY: 0.0000540 AC XY: 4 AN XY: 74136

Gnomad4 AFR AF: 0.0000484

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000226 Hom.: 0

Bravo AF: 0.0000718

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-IV-A Pathogenic:5 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1998	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Likely pathogenic, criteria provided, single submitter	research	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	Feb 01, 2021	In vivo and in vitro functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; low in vitro enzymatic activity; 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) -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The GALNS c.337A>T (p.Ile113Phe) missense variant is described as the second most frequently reported pathogenic variant, accounting for five percent of mucopolysaccharidosis type IV type A patient alleles (Morrone et al. 2014), and is especially common among patients of British and Irish descent. Across a selection of the available literature, the p.Ile113Phe variant has been identified in a homozygous state in two patients with mucopolysaccharidosis type IV, in a compound heterozygous state in 11 patients, and in a heterozygous state in six patients (Tomatsu et al. 1995; Yamada et al. 1998; Tomatsu et al. 2004; Dung et al. 2013; Bhattacharya et al. 2014). The p.Ile113Phe variant was absent from 300 control chromosomes (Tomatsu et al. 1995; Yamada et al. 1998; Tomatsu et al. 2004) and is reported at a frequency of 0.00012 in the European American population of the Exome Sequencing Project; however, this frequency is based on one allele only in a region of good sequence coverage, suggesting the variant is rare. In vitro transient expression studies showed that the p.Ile113Phe variant reduced cDNA expression to approximately five percent of wild type (Tomatsu et al. 1995; Sukegawa et al. 2000). Based on the collective evidence, the p.Ile113Phe variant is classified as 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 isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 113 of the GALNS protein (p.Ile113Phe). This variant is present in population databases (rs118204438, gnomAD 0.009%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 7668283, 25137622; Invitae). ClinVar contains an entry for this variant (Variation ID: 703). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GALNS protein function. Experimental studies have shown that this missense change affects GALNS function (PMID: 7668283). 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

Jul 03, 2019

Variant summary: GALNS c.337A>T (p.Ile113Phe) 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 4e-05 in 250984 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in GALNS causing Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (4e-05 vs 0.002), allowing no conclusion about variant significance. c.337A>T has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (Yamada_1998, Tomatsu_2004, Dung_2013). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating the effects of the variant on protein function. The most pronounced variant effect results in <10% of normal activity (Yamada_1998, Sukegawa_2000). Two ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 22, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Benign	19
Dann	Benign	0.54
DEOGEN2	Uncertain	0.71	D;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.92	L;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.9	N;N
REVEL	Pathogenic	0.71
Sift	Uncertain	0.024	D;D
Sift4G	Benign	0.29	T;.
Polyphen		0.99	D;.
Vest4		0.90
MVP		0.99
MPC		0.55
ClinPred		0.20	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.70
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs118204438; hg19: chr16-88907485;