16-88837678-A-G

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.510T>C(p.Tyr170Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0383 in 1,613,984 control chromosomes in the GnomAD database, including 1,423 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.039 ( 150 hom., cov: 32)

Exomes 𝑓: 0.038 ( 1273 hom. )

Consequence

GALNS
NM_000512.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.141

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 16-88837678-A-G is Benign according to our data. Variant chr16-88837678-A-G is described in ClinVar as Benign. ClinVar VariationId is 93180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0773 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000512.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GALNS	NM_000512.5	MANE Select	c.510T>C	p.Tyr170Tyr	synonymous	Exon 5 of 14	NP_000503.1
GALNS	NM_001323544.2		c.528T>C	p.Tyr176Tyr	synonymous	Exon 6 of 15	NP_001310473.1
GALNS	NM_001323543.2		c.-46T>C		5_prime_UTR	Exon 4 of 13	NP_001310472.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GALNS	ENST00000268695.10	TSL:1 MANE Select	c.510T>C	p.Tyr170Tyr	synonymous	Exon 5 of 14	ENSP00000268695.5
GALNS	ENST00000562593.5	TSL:1	n.3919T>C		non_coding_transcript_exon	Exon 3 of 12
GALNS	ENST00000562831.1	TSL:3	c.294T>C	p.Tyr98Tyr	synonymous	Exon 4 of 6	ENSP00000455174.1

Frequencies

GnomAD3 genomes

AF:

0.0388

AC:

5903

AN:

152114

Hom.:

149

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0318

Gnomad AMI

AF:

0.0822

Gnomad AMR

AF:

0.0696

Gnomad ASJ

AF:

0.0374

Gnomad EAS

AF:

0.0313

Gnomad SAS

AF:

0.0840

Gnomad FIN

AF:

0.0192

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0357

Gnomad OTH

AF:

0.0469

GnomAD2 exomes

AF:

0.0457

AC:

11487

AN:

251426

AF XY:

0.0473

show subpopulations

Gnomad AFR exome

AF:

0.0323

Gnomad AMR exome

AF:

0.0672

Gnomad ASJ exome

AF:

0.0346

Gnomad EAS exome

AF:

0.0352

Gnomad FIN exome

AF:

0.0215

Gnomad NFE exome

AF:

0.0391

Gnomad OTH exome

AF:

0.0451

GnomAD4 exome

AF:

0.0383

AC:

55960

AN:

1461752

Hom.:

1273

Cov.:

AF XY:

0.0395

AC XY:

28716

AN XY:

727178

show subpopulations

African (AFR)

AF:

0.0308

AC:

1030

AN:

33478

American (AMR)

AF:

0.0656

AC:

2936

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0337

AC:

880

AN:

26136

East Asian (EAS)

AF:

0.0422

AC:

1675

AN:

39698

South Asian (SAS)

AF:

0.0786

AC:

6781

AN:

86250

European-Finnish (FIN)

AF:

0.0227

AC:

1209

AN:

53350

Middle Eastern (MID)

AF:

0.0570

AC:

328

AN:

5750

European-Non Finnish (NFE)

AF:

0.0349

AC:

38813

AN:

1111972

Other (OTH)

AF:

0.0382

AC:

2308

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

2983

5966

8949

11932

14915

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1482

2964

4446

5928

7410

<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:

0.0389

AC:

5917

AN:

152232

Hom.:

150

Cov.:

AF XY:

0.0396

AC XY:

2945

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.0319

AC:

1326

AN:

41544

American (AMR)

AF:

0.0700

AC:

1070

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0374

AC:

130

AN:

3472

East Asian (EAS)

AF:

0.0306

AC:

158

AN:

5170

South Asian (SAS)

AF:

0.0840

AC:

405

AN:

4820

European-Finnish (FIN)

AF:

0.0192

AC:

204

AN:

10620

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0357

AC:

2427

AN:

68006

Other (OTH)

AF:

0.0478

AC:

101

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

293

586

878

1171

1464

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<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:

0.0365

Hom.:

Bravo

AF:

0.0410

Asia WGS

AF:

0.0710

AC:

248

AN:

3478

EpiCase

AF:

0.0399

EpiControl

AF:

0.0401

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

Feb 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.510T>C alters a non-conserved nucleotide resulting in a synonymous change. 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 0.046 in 121120 control chromosomes in the ExAC database, including 159 homozygotes. The observed variant frequency is approximately 22-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. Two ClinVar submission from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign.

Nov 12, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mucopolysaccharidosis, MPS-IV-A

Benign:3

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

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.

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Oct 23, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jun 25, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24035930, 9452036)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.98

(source)

DANN

Benign

0.81

PhyloP100

-0.14

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over