rs148565559

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4

Conservation

PhyloP100: 6.99

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13681221).

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALNS	NM_000512.5 link	c.499T>G	p.Phe167Val	missense_variant	Exon 5 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.499T>G	p.Phe167Val	missense_variant	Exon 5 of 14	1	NM_000512.5	ENSP00000268695.5		P34059

Frequencies

GnomAD3 genomes

AF:

0.00117

AC:

178

AN:

152166

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00100

AC XY:

136

AN XY:

135886

show subpopulations

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.:

Cov.:

AF XY:

0.00156

AC XY:

1132

AN XY:

727206

show subpopulations

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.:

Cov.:

AF XY:

0.00109

AC XY:

AN XY:

74466

show subpopulations

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.:

Bravo

AF:

0.00118

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.000898

AC:

109

EpiCase

AF:

0.00153

EpiControl

AF:

0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-IV-A

Uncertain:3

Feb 01, 2021

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

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) -

Oct 30, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 07, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Dec 15, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM2, PM3_supporting, PS3 -

not specified

Uncertain:1

Aug 06, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This frequency is similar to the estimated for a pathogenic variant in GALNS causing Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (0.0016 vs 0.002). 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

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.81

D;.

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.88

D;D

M_CAP

Pathogenic

0.89

MetaRNN

Benign

0.14

T;T

MetaSVM

Pathogenic

0.96

MutationAssessor

Benign

0.98

L;.

PrimateAI

Uncertain

0.67

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

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

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