rs114703967

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000512.5(GALNS):c.1376C>T(p.Ala459Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00632 in 1,573,198 control chromosomes in the GnomAD database, including 542 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A459T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.032 ( 256 hom., cov: 33)

Exomes 𝑓: 0.0035 ( 286 hom. )

Consequence

GALNS
NM_000512.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.266

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 was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017710924).

BP6

Variant 16-88818113-G-A is Benign according to our data. Variant chr16-88818113-G-A is described in ClinVar as [Benign]. Clinvar id is 321189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALNS	NM_000512.5 link	c.1376C>T	p.Ala459Val	missense_variant	Exon 13 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.1376C>T	p.Ala459Val	missense_variant	Exon 13 of 14	1	NM_000512.5	ENSP00000268695.5		P34059

Frequencies

GnomAD3 genomes

AF:

0.0324

AC:

4932

AN:

152146

Hom.:

256

Cov.:

show subpopulations

Gnomad AFR

AF:

0.114

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00949

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.0258

GnomAD2 exomes

AF:

0.00912

AC:

1761

AN:

193128

AF XY:

0.00633

show subpopulations

Gnomad AFR exome

AF:

0.123

Gnomad AMR exome

AF:

0.00648

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000113

Gnomad NFE exome

AF:

0.000395

Gnomad OTH exome

AF:

0.00431

GnomAD4 exome

AF:

0.00352

AC:

5008

AN:

1420934

Hom.:

286

Cov.:

AF XY:

0.00301

AC XY:

2120

AN XY:

704400

show subpopulations

Gnomad4 AFR exome

AF:

0.121

AC:

4016

AN:

33216

Gnomad4 AMR exome

AF:

0.00644

AC:

253

AN:

39286

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

25450

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

38682

Gnomad4 SAS exome

AF:

0.000208

AC:

AN:

81692

Gnomad4 FIN exome

AF:

0.0000259

AC:

AN:

38582

Gnomad4 NFE exome

AF:

0.000234

AC:

257

AN:

1099028

Gnomad4 Remaining exome

AF:

0.00748

AC:

444

AN:

59360

Heterozygous variant carriers

228

455

683

910

1138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

118

236

354

472

590

<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:

0.0324

AC:

4940

AN:

152264

Hom.:

256

Cov.:

AF XY:

0.0311

AC XY:

2319

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.113

AC:

0.113445

AN:

0.113445

Gnomad4 AMR

AF:

0.00948

AC:

0.00948084

AN:

0.00948084

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00104

AC:

0.0010352

AN:

0.0010352

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.000353

AC:

0.000352796

AN:

0.000352796

Gnomad4 OTH

AF:

0.0255

AC:

0.0255198

AN:

0.0255198

Heterozygous variant carriers

229

459

688

918

1147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

116

174

232

290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00878

Hom.:

Bravo

AF:

0.0374

ESP6500AA

AF:

0.113

AC:

494

ESP6500EA

AF:

0.000701

AC:

ExAC

AF:

0.00939

AC:

1122

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-IV-A

Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Apr 24, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 13, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified

Benign:1

Oct 30, 2017

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The GALNS c.1376C>T (p.Ala459Val) variant involves the alteration of a non-conserved nucleotide and 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 2649/218538 control chromosomes (gnomAD), predominantly observed in the African subpopulation at a frequency of 0.119713 (2406/20098). This frequency is about 59 times the estimated maximal expected allele frequency of a pathogenic GALNS variant (0.0020412), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. A publication, Bunge_1997, cites the variant of interest in an affected individual, who was homozygote for a pathogenic GALNS variant, G47R. In addition, multiple clinical diagnostic laboratories classified this variant as likely benign/benign. Taken together, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.40

CADD

Benign

1.5

DANN

Benign

0.94

DEOGEN2

Uncertain

0.74

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.069

LIST_S2

Benign

0.21

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.5

PrimateAI

Benign

0.23

PROVEAN

Benign

-2.1

REVEL

Benign

0.11

Sift

Benign

0.20

Sift4G

Benign

0.28

Polyphen

0.047

Vest4

0.12

MVP

0.74

MPC

0.097

ClinPred

0.0036

GERP RS

-4.9

Varity_R

0.070

gMVP

0.33

Mutation Taster

=87/13

polymorphism (auto)

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