rs35232749

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000512.5(GALNS):c.846C>T(p.Phe282Phe) 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 1,610,646 control chromosomes in the GnomAD database, including 1,421 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.039 ( 147 hom., cov: 32)

Exomes 𝑓: 0.038 ( 1274 hom. )

Consequence

GALNS
NM_000512.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0650

Publications

5 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 -21 ACMG points.

BP4

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

BP6

Variant 16-88835265-G-A is Benign according to our data. Variant chr16-88835265-G-A is described in ClinVar as Benign. ClinVar VariationId is 93187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.065 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0768 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALNS	NM_000512.5 link	c.846C>T	p.Phe282Phe	synonymous_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.846C>T	p.Phe282Phe	synonymous_variant	Exon 8 of 14	1	NM_000512.5	ENSP00000268695.5		P34059

Frequencies

GnomAD3 genomes

AF:

0.0390

AC:

5941

AN:

152142

Hom.:

146

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0318

Gnomad AMI

AF:

0.0822

Gnomad AMR

AF:

0.0710

Gnomad ASJ

AF:

0.0372

Gnomad EAS

AF:

0.0304

Gnomad SAS

AF:

0.0835

Gnomad FIN

AF:

0.0191

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0361

Gnomad OTH

AF:

0.0473

GnomAD2 exomes

AF:

0.0458

AC:

11223

AN:

245130

AF XY:

0.0475

show subpopulations

Gnomad AFR exome

AF:

0.0311

Gnomad AMR exome

AF:

0.0685

Gnomad ASJ exome

AF:

0.0343

Gnomad EAS exome

AF:

0.0346

Gnomad FIN exome

AF:

0.0212

Gnomad NFE exome

AF:

0.0396

Gnomad OTH exome

AF:

0.0447

GnomAD4 exome

AF:

0.0383

AC:

55806

AN:

1458386

Hom.:

1274

Cov.:

AF XY:

0.0395

AC XY:

28617

AN XY:

725128

show subpopulations

African (AFR)

AF:

0.0306

AC:

1022

AN:

33442

American (AMR)

AF:

0.0669

AC:

2960

AN:

44240

Ashkenazi Jewish (ASJ)

AF:

0.0336

AC:

871

AN:

25944

East Asian (EAS)

AF:

0.0416

AC:

1651

AN:

39648

South Asian (SAS)

AF:

0.0777

AC:

6643

AN:

85448

European-Finnish (FIN)

AF:

0.0226

AC:

1201

AN:

53206

Middle Eastern (MID)

AF:

0.0562

AC:

324

AN:

5762

European-Non Finnish (NFE)

AF:

0.0350

AC:

38837

AN:

1110428

Other (OTH)

AF:

0.0381

AC:

2297

AN:

60268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

3453

6906

10359

13812

17265

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1480

2960

4440

5920

7400

<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:

0.0391

AC:

5958

AN:

152260

Hom.:

147

Cov.:

AF XY:

0.0398

AC XY:

2964

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.0319

AC:

1325

AN:

41556

American (AMR)

AF:

0.0714

AC:

1093

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0372

AC:

129

AN:

3468

East Asian (EAS)

AF:

0.0301

AC:

156

AN:

5182

South Asian (SAS)

AF:

0.0836

AC:

402

AN:

4810

European-Finnish (FIN)

AF:

0.0191

AC:

203

AN:

10614

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0361

AC:

2455

AN:

68006

Other (OTH)

AF:

0.0482

AC:

102

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

294

588

881

1175

1469

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:

0.0385

Hom.:

107

Bravo

AF:

0.0413

Asia WGS

AF:

0.0690

AC:

239

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

- -

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.846C>T 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 0.062 in 84726 control chromosomes in the gnomAD database, including 143 homozygotes. The observed variant frequency is approximately 30-folds higher than 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 submissions 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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 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

- -

not provided

Benign:3

May 01, 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. -

Oct 22, 2015

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.67

(source)

DANN

Benign

0.58

PhyloP100

0.065

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over