rs770053354

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000512.5(GALNS):c.860C>T(p.Ser287Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000871 in 1,606,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S287S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

GALNS
NM_000512.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 9.74

Publications

18 publications found

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 Gene-Disease associations (from GenCC):

mucopolysaccharidosis type 4A
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

GALNS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_000512.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 16-88835251-G-A is Pathogenic according to our data. Variant chr16-88835251-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 265169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALNS	NM_000512.5 link	c.860C>T	p.Ser287Leu	missense_variant	Exon 8 of 14	ENST00000268695.10	NP_000503.1	P34059Q96I49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALNS	ENST00000268695.10 link	c.860C>T	p.Ser287Leu	missense_variant	Exon 8 of 14	1	NM_000512.5	ENSP00000268695.5		P34059

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000168

AC:

AN:

238398

AF XY:

0.0000233

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000300

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000187

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000894

AC:

AN:

1454236

Hom.:

Cov.:

AF XY:

0.00000969

AC XY:

AN XY:

722608

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33408

American (AMR)

AF:

0.0000229

AC:

AN:

43716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25824

East Asian (EAS)

AF:

0.00

AC:

AN:

39558

South Asian (SAS)

AF:

0.0000118

AC:

AN:

84832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52860

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00000902

AC:

AN:

1108142

Other (OTH)

AF:

0.0000166

AC:

AN:

60142

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-IV-A

Pathogenic:9

Feb 05, 2020

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 01, 2021

Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

In vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; 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) -

Jul 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 287 of the GALNS protein (p.Ser287Leu). This variant is present in population databases (rs770053354, gnomAD 0.003%). This missense change has been observed in individual(s) with mucopolysaccharidosis IV type A (PMID: 9298823, 15235041, 16287098, 23876334, 25252036, 29731656). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 265169). 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. -

Nov 14, 2018

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM3,PP2,PP3. -

Nov 07, 2021

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 14, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jun 10, 2022

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 31, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense c.860C>T (p.Ser287Leu) variant in the GALNS gene has been observed in individual(s) with mucopolysaccharidosis IV type A (Tomatsu, Shunji et al., 2005). Mapping of the p.Ser287Leu variant to the X-ray crystallography structure of the GALNS protein found that this variant is buried within the protein and likely results in loss of proper hydrogen bonding (Rivera-Colon et al., 2012). This variant is reported with the allele frequency (0.001%) in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). The amino acid Serine at position 287 is changed to a Leucine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Ser287Leu in GALNS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:3

Mar 16, 2015

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The S287L missense variant has been reported previously in association with MPS IVA in a patient with a severe MPS IVA phenotype who was homozygous for the S287L variant (Bunge et al., 1997). Mapping of the S287L variant to the X-ray crystallography structure of the GALNS protein found that this variant is buried within the protein and likely results in loss of proper hydrogen bonding (Rivera-Colon et al., 2012). Furthermore, S287L is a non-conservative amino acid substitution, which occurs at a position that is highly conserved across species, and missense variants in nearby residues (F284V, N289D, N289S, G290R, G290S) have also been reported in the Human Gene Mutation Database in association with MPS IVA (Stenson et al., 2014), further supporting the functional importance of this region of the protein. Therefore, we interpret S287L to be a pathogenic variant. -

Dec 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Morquio syndrome

Pathogenic:1

Nov 03, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Ser287Leu variant in GALNS has been reported in at least 2 homozygous and 2 compound heterozygous individuals with severe mucopolysaccharidosis IVa (Bunge 1997 PMID: 9298823, Tuysuz 2019 PMID: 30980944, Zanetti 2020 PMID: 32036093). It has also been reported in ClinVar (Variation ID 265169) and identified in 1/41450 African chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Mapping of the variant to the X-ray crystallography structure of the GALNS protein found that this variant is buried within the protein and likely results in loss of proper hydrogen bonding (Rivera-Colon 2012 PMID: 22940367). In summary, this variant meets criteria to be classified as Likely pathogenic for autosomal recessive mucopolysaccharidosis IVa. ACMG/AMP Criteria applied: PM3_Strong, PM2_Supporting, PP3, PS3_Supporting, PP4. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

Eigen

Pathogenic

0.78

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

PhyloP100

9.7

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-5.9

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.98

MVP

1.0

MPC

0.48

ClinPred

1.0

GERP RS

5.1

Varity_R

0.98

gMVP

0.99

Mutation Taster

=7/93

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over