16-88835791-G-C

Variant names:

• chr16-88835791-G-C
• rs34745339
• NM_000512.5:c.692C>G

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.692C>G​(p.Ala231Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0553 in 1,614,094 control chromosomes in the GnomAD database, including 2,937 homozygotes. In-silico tool predicts 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. A231V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.049 (244 hom., cov: 33)
  • Exomes 𝑓: 0.056 (2693 hom.)
• Consequence: GALNS NM_000512.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 9.52
• Publications: 18 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 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000512.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.004372239).
• BP6: Variant 16-88835791-G-C is Benign according to our data. Variant chr16-88835791-G-C is described in ClinVar as Benign. ClinVar VariationId is 93183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0743 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALNS	NM_000512.5	MANE Select	c.692C>G	p.Ala231Gly	missense	Exon 7 of 14	NP_000503.1
	GALNS	NM_001323544.2		c.710C>G	p.Ala237Gly	missense	Exon 8 of 15	NP_001310473.1
	GALNS	NM_001323543.2		c.137C>G	p.Ala46Gly	missense	Exon 6 of 13	NP_001310472.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALNS	ENST00000268695.10	TSL:1 MANE Select	c.692C>G	p.Ala231Gly	missense	Exon 7 of 14	ENSP00000268695.5
	GALNS	ENST00000562593.5	TSL:1	n.4101C>G		non_coding_transcript_exon	Exon 5 of 12
	GALNS	ENST00000562831.1	TSL:3	c.476C>G	p.Ala159Gly	missense	Exon 6 of 6	ENSP00000455174.1

Frequencies

GnomAD3 genomes AF: 0.0495 AC: 7535 AN: 152204 Hom.: 243 Cov.: 33

Gnomad AFR AF: 0.0340

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0491

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0808

Gnomad FIN AF: 0.0229

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.0606

Gnomad OTH AF: 0.0588

GnomAD2 exomes AF: 0.0519 AC: 13037 AN: 251332 AF XY: 0.0548

Gnomad AFR exome AF: 0.0356

Gnomad AMR exome AF: 0.0339

Gnomad ASJ exome AF: 0.123

Gnomad EAS exome AF: 0.000489

Gnomad FIN exome AF: 0.0231

Gnomad NFE exome AF: 0.0599

Gnomad OTH exome AF: 0.0607

GnomAD4 exome AF: 0.0559 AC: 81652 AN: 1461772 Hom.: 2693 Cov.: 44 AF XY: 0.0575 AC XY: 41784 AN XY: 727180

African (AFR) AF: 0.0361 AC: 1207 AN: 33480

American (AMR) AF: 0.0386 AC: 1725 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 3278 AN: 26132

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39698

South Asian (SAS) AF: 0.0811 AC: 6996 AN: 86250

European-Finnish (FIN) AF: 0.0234 AC: 1248 AN: 53354

Middle Eastern (MID) AF: 0.107 AC: 618 AN: 5766

European-Non Finnish (NFE) AF: 0.0568 AC: 63214 AN: 1111976

Other (OTH) AF: 0.0557 AC: 3361 AN: 60394

GnomAD4 genome AF: 0.0494 AC: 7529 AN: 152322 Hom.: 244 Cov.: 33 AF XY: 0.0484 AC XY: 3606 AN XY: 74490

African (AFR) AF: 0.0338 AC: 1406 AN: 41564

American (AMR) AF: 0.0490 AC: 750 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 415 AN: 3470

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5184

South Asian (SAS) AF: 0.0809 AC: 391 AN: 4834

European-Finnish (FIN) AF: 0.0229 AC: 243 AN: 10630

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.0606 AC: 4121 AN: 68018

Other (OTH) AF: 0.0582 AC: 123 AN: 2114

Alfa AF: 0.0484 Hom.: 94

Bravo AF: 0.0496

TwinsUK AF: 0.0550 AC: 204

ALSPAC AF: 0.0592 AC: 228

ESP6500AA AF: 0.0369 AC: 162

ESP6500EA AF: 0.0607 AC: 522

ExAC AF: 0.0517 AC: 6271

Asia WGS AF: 0.0300 AC: 104 AN: 3478

EpiCase AF: 0.0656

EpiControl AF: 0.0644

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-IV-A Benign:4

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 07, 2021

Genome-Nilou Lab

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.

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:3

Jun 16, 2017

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.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 26, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0044	T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	0.085	N
PhyloP100		9.5
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.042	D
Polyphen		0.63	P
Vest4		0.28
MPC		0.39
ClinPred		0.023	T
GERP RS		5.0
Varity_R		0.80
gMVP		0.91
Mutation Taster		=29/71	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs34745339; hg19: chr16-88902199; COSMIC: COSV107276876; COSMIC: COSV107276876;