rs118204443

Positions:

chr16-88832099-C-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000512.5(GALNS):c.901G>T(p.Gly301Cys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000849 in 1,613,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000082 ( 0 hom. )

Consequence

GALNS
NM_000512.5 missense, splice_region

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 7.77

Variant links:

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]

GALNS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.962

PP5

Variant 16-88832099-C-A is Pathogenic according to our data. Variant chr16-88832099-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88832099-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALNS	NM_000512.5 linkuse as main transcript	c.901G>T	p.Gly301Cys	missense_variant, splice_region_variant	9/14	ENST00000268695.10	NP_000503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALNS	ENST00000268695.10 linkuse as main transcript	c.901G>T	p.Gly301Cys	missense_variant, splice_region_variant	9/14	1	NM_000512.5	ENSP00000268695	P1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.000118

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000442

AC:

AN:

249100

Hom.:

AF XY:

0.0000444

AC XY:

AN XY:

135044

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000581

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:

0.0000623

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.0000821

AC:

120

AN:

1461294

Hom.:

Cov.:

AF XY:

0.0000770

AC XY:

AN XY:

726942

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000895

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:

0.000103

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000112

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000827

Hom.:

Bravo

AF:

0.000110

ExAC

AF:

0.0000989

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-IV-A

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 301 of the GALNS protein (p.Gly301Cys). This variant is present in population databases (rs118204443, gnomAD 0.008%). This missense change has been observed in individuals with mucopolysaccharidosis IVA (PMID: 9298823, 9385378, 15235041, 23876334). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 708). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects GALNS function (PMID: 10814710, 17876718). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1997	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	research	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	Feb 01, 2021	In vitro and in vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; low to null in vitro enzymatic activity; PS3_strong); 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	Revvity Omics, Revvity	Jun 30, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili	Aug 14, 2024	MetaRNN = 0.962 is greater than 0.939=strong pathogenic(PP3).Combined evidence strength is Strong.ClinVar classifies this variant as Pathogenic, 2 stars Supporting: UniProt Variants classifies this variant as Pathogenic. LOVD classifies this variant as Pathogenic (PP5). Alternative variant chr16:88832098 C>T (Gly307Asp) is classified Likely Pathogenic, 1 star, by ClinVar (PM5). GnomAD genomes homozygous allele count = 0 is less than 2 for AR gene GALNS. GnomAD exomes homozygous allele count = 0 is less than 2 for AR gene GALNS (PM2). We identified this variant in compound heterozygosity in a 7-year-old girl with a phenotype of Mucopolysaccharidosis IVA. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 20, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Sep 15, 2021	- -

Morquio syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Apr 24, 2018

Variant summary: GALNS c.901G>T (p.Gly301Cys) 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 0.00011 in 111042 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in GALNS causing Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (0.00011 vs 0.002), allowing no conclusion about variant significance. The variant, c.901G>T has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (e.g. Kato 1997, Bunge 1997, Dung 2013). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Kato 1997). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.5

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-7.8

REVEL

Pathogenic

0.98

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.97

MVP

1.0

MPC

0.52

ClinPred

0.98

GERP RS

5.2

Varity_R

0.96

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over