rs114703967

Variant names:

• chr16-88818113-G-A
• rs114703967
• NM_000512.5:c.1376C>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.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. 16/21 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.266
• Publications: 6 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 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000512.5
• 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 VariationId 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	c.1376C>T	p.Ala459Val	missense_variant	Exon 13 of 14	ENST00000268695.10	NP_000503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALNS	ENST00000268695.10	c.1376C>T	p.Ala459Val	missense_variant	Exon 13 of 14	1	NM_000512.5	ENSP00000268695.5

Frequencies

GnomAD3 genomes AF: 0.0324 AC: 4932 AN: 152146 Hom.: 256 Cov.: 33

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

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.: 33 AF XY: 0.00301 AC XY: 2120 AN XY: 704400

African (AFR) AF: 0.121 AC: 4016 AN: 33216

American (AMR) AF: 0.00644 AC: 253 AN: 39286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25450

East Asian (EAS) AF: 0.00 AC: 0 AN: 38682

South Asian (SAS) AF: 0.000208 AC: 17 AN: 81692

European-Finnish (FIN) AF: 0.0000259 AC: 1 AN: 38582

Middle Eastern (MID) AF: 0.00355 AC: 20 AN: 5638

European-Non Finnish (NFE) AF: 0.000234 AC: 257 AN: 1099028

Other (OTH) AF: 0.00748 AC: 444 AN: 59360

GnomAD4 genome AF: 0.0324 AC: 4940 AN: 152264 Hom.: 256 Cov.: 33 AF XY: 0.0311 AC XY: 2319 AN XY: 74462

African (AFR) AF: 0.113 AC: 4710 AN: 41518

American (AMR) AF: 0.00948 AC: 145 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68028

Other (OTH) AF: 0.0255 AC: 54 AN: 2116

Alfa AF: 0.00878 Hom.: 80

Bravo AF: 0.0374

ESP6500AA AF: 0.113 AC: 494

ESP6500EA AF: 0.000701 AC: 6

ExAC AF: 0.00939 AC: 1122

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 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

- -

not provided Benign:3

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. -

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

- -

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	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	1.5
DANN	Benign	0.94
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.21	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.27
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.11
Sift	Benign	0.20	T
Sift4G	Benign	0.28	T
Polyphen		0.047	B
Vest4		0.12
MVP		0.74
MPC		0.097
ClinPred		0.0036	T
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

Other links and lift over

dbSNP: rs114703967; hg19: chr16-88884521;