NM_000512.5:c.318C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4BP6_Very_StrongBP7BS1BS2

The NM_000512.5(GALNS):c.318C>T(p.Asn106Asn) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0233 in 1,612,518 control chromosomes in the GnomAD database, including 477 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 50 hom., cov: 33)

Exomes 𝑓: 0.024 ( 427 hom. )

Consequence

GALNS
NM_000512.5 splice_region, synonymous

Scores

Splicing: ADA: 0.002116

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.902

Publications

6 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: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.187).

BP6

Variant 16-88841898-G-A is Benign according to our data. Variant chr16-88841898-G-A is described in ClinVar as [Benign]. Clinvar id is 256333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.902 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0194 (2948/152278) while in subpopulation NFE AF = 0.0295 (2008/68014). AF 95% confidence interval is 0.0284. There are 50 homozygotes in GnomAd4. There are 1412 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 50 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALNS	NM_000512.5 link	c.318C>T	p.Asn106Asn	splice_region_variant, synonymous_variant	Exon 3 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.318C>T	p.Asn106Asn	splice_region_variant, synonymous_variant	Exon 3 of 14	1	NM_000512.5	ENSP00000268695.5		P34059

Frequencies

GnomAD3 genomes

AF:

0.0194

AC:

2946

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00628

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0256

Gnomad ASJ

AF:

0.0231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00434

Gnomad FIN

AF:

0.0116

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0295

Gnomad OTH

AF:

0.0263

GnomAD2 exomes

AF:

0.0184

AC:

4535

AN:

245878

AF XY:

0.0188

show subpopulations

Gnomad AFR exome

AF:

0.00535

Gnomad AMR exome

AF:

0.0179

Gnomad ASJ exome

AF:

0.0198

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0117

Gnomad NFE exome

AF:

0.0282

Gnomad OTH exome

AF:

0.0207

GnomAD4 exome

AF:

0.0237

AC:

34632

AN:

1460240

Hom.:

427

Cov.:

AF XY:

0.0235

AC XY:

17081

AN XY:

726318

show subpopulations

African (AFR)

AF:

0.00469

AC:

157

AN:

33456

American (AMR)

AF:

0.0184

AC:

820

AN:

44572

Ashkenazi Jewish (ASJ)

AF:

0.0211

AC:

552

AN:

26112

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39652

South Asian (SAS)

AF:

0.00453

AC:

389

AN:

85926

European-Finnish (FIN)

AF:

0.0131

AC:

695

AN:

53128

Middle Eastern (MID)

AF:

0.0233

AC:

134

AN:

5760

European-Non Finnish (NFE)

AF:

0.0275

AC:

30557

AN:

1111326

Other (OTH)

AF:

0.0220

AC:

1326

AN:

60308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

1795

3590

5386

7181

8976

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0194

AC:

2948

AN:

152278

Hom.:

Cov.:

AF XY:

0.0190

AC XY:

1412

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00631

AC:

262

AN:

41546

American (AMR)

AF:

0.0256

AC:

391

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0231

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00435

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0116

AC:

123

AN:

10616

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0295

AC:

2008

AN:

68014

Other (OTH)

AF:

0.0261

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

154

307

461

614

768

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0257

Hom.:

222

Bravo

AF:

0.0190

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 15, 2019

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: GALNS c.318C>T (p.Asn106Asn) alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.018 in 245878 control chromosomes in the gnomAD database, including 68 homozygotes. The observed variant frequency is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in GALNS causing Mucopolysaccharidosis Type IVA (Morquio Syndrome A) phenotype (0.002), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.318C>T in individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2x Benign, 1x VUS). Based on the evidence outlined above, the variant was classified as benign. -

Nov 06, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 03, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 9298823, 22521955) -

Jun 21, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

1.1

(source)

DANN

Benign

0.90

PhyloP100

-0.90

Mutation Taster

=67/33

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0021

dbscSNV1_RF

Benign

0.25

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

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NM_000512.5:c.318C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over