rs2303269

Variant names:

• chr16-88824832-C-A
• rs2303269
• NM_000512.5:c.1177G>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000512.5(GALNS):​c.1177G>T​(p.Ala393Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0521 in 1,613,270 control chromosomes in the GnomAD database, including 2,482 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.054 (257 hom., cov: 33)
  • Exomes 𝑓: 0.052 (2225 hom.)
• Consequence: GALNS NM_000512.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 3.60
• Publications: 22 publications found

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

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_000512.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0041275322).
• BP6: Variant 16-88824832-C-A is Benign according to our data. Variant chr16-88824832-C-A is described in ClinVar as Benign. ClinVar VariationId is 93165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0866 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALNS	NM_000512.5	c.1177G>T	p.Ala393Ser	missense_variant	Exon 11 of 14	ENST00000268695.10	NP_000503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALNS	ENST00000268695.10	c.1177G>T	p.Ala393Ser	missense_variant	Exon 11 of 14	1	NM_000512.5	ENSP00000268695.5

Frequencies

GnomAD3 genomes AF: 0.0535 AC: 8146 AN: 152184 Hom.: 256 Cov.: 33

Gnomad AFR AF: 0.0417

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.0819

Gnomad ASJ AF: 0.0498

Gnomad EAS AF: 0.0574

Gnomad SAS AF: 0.0936

Gnomad FIN AF: 0.0593

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0495

Gnomad OTH AF: 0.0632

GnomAD2 exomes AF: 0.0617 AC: 15403 AN: 249724 AF XY: 0.0635

Gnomad AFR exome AF: 0.0410

Gnomad AMR exome AF: 0.0774

Gnomad ASJ exome AF: 0.0479

Gnomad EAS exome AF: 0.0604

Gnomad FIN exome AF: 0.0568

Gnomad NFE exome AF: 0.0548

Gnomad OTH exome AF: 0.0596

GnomAD4 exome AF: 0.0520 AC: 75920 AN: 1460968 Hom.: 2225 Cov.: 32 AF XY: 0.0530 AC XY: 38486 AN XY: 726746

African (AFR) AF: 0.0400 AC: 1339 AN: 33478

American (AMR) AF: 0.0767 AC: 3428 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0460 AC: 1203 AN: 26136

East Asian (EAS) AF: 0.0678 AC: 2693 AN: 39696

South Asian (SAS) AF: 0.0883 AC: 7620 AN: 86254

European-Finnish (FIN) AF: 0.0561 AC: 2952 AN: 52656

Middle Eastern (MID) AF: 0.0651 AC: 375 AN: 5764

European-Non Finnish (NFE) AF: 0.0478 AC: 53109 AN: 1111894

Other (OTH) AF: 0.0530 AC: 3201 AN: 60370

GnomAD4 genome AF: 0.0536 AC: 8165 AN: 152302 Hom.: 257 Cov.: 33 AF XY: 0.0553 AC XY: 4118 AN XY: 74466

African (AFR) AF: 0.0418 AC: 1739 AN: 41572

American (AMR) AF: 0.0823 AC: 1259 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0498 AC: 173 AN: 3472

East Asian (EAS) AF: 0.0570 AC: 295 AN: 5178

South Asian (SAS) AF: 0.0937 AC: 452 AN: 4824

European-Finnish (FIN) AF: 0.0593 AC: 630 AN: 10616

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0495 AC: 3368 AN: 68026

Other (OTH) AF: 0.0640 AC: 135 AN: 2110

Alfa AF: 0.0513 Hom.: 173

Bravo AF: 0.0535

TwinsUK AF: 0.0472 AC: 175

ALSPAC AF: 0.0462 AC: 178

ESP6500AA AF: 0.0434 AC: 191

ESP6500EA AF: 0.0493 AC: 424

ExAC AF: 0.0615 AC: 7463

Asia WGS AF: 0.0820 AC: 286 AN: 3478

EpiCase AF: 0.0512

EpiControl AF: 0.0524

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-IV-A Benign:4

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

- -

Feb 01, 2021

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

Allele frequency is >5% in gnomAD v2.1.1 (BA1_stand-alone); allele frequency is greater than expected for disorder (BS1_strong); multiple lines of computational evidence suggest no impact on gene or gene product (BP4_supporting) -

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 specified Benign:3

Oct 24, 2017

Eurofins Ntd Llc (ga)

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.1177G>T (p.Ala393Ser) results in a conservative amino acid change located in the Sulfatase, N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.06 in 275882 control chromosomes in the gnomAD database, including 553 homozygotes. The observed variant frequency is approximately 29-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. Three 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. -

-

PreventionGenetics, part of Exact Sciences

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 25, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25252036, 24035930, 16837223, 21251309, 15235041, 15241807, 9452036) -

Oct 22, 2015

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
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	15
DANN	Benign	0.90
DEOGEN2	Uncertain	0.69	D
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.72
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.6
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.20
Sift	Uncertain	0.014	D
Sift4G	Benign	0.082	T
Polyphen		0.020	B
Vest4		0.11
MPC		0.091
ClinPred		0.021	T
GERP RS		1.6
Varity_R		0.16
gMVP		0.84
Mutation Taster		=95/5	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

Other links and lift over

dbSNP: rs2303269; hg19: chr16-88891240; COSMIC: COSV51936235;