16-88835868-C-T

Variant names:

• chr16-88835868-C-T
• rs12934499
• NM_000512.5:c.634-19G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000512.5(GALNS):​c.634-19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.25 in 1,613,322 control chromosomes in the GnomAD database, including 54,425 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.22 (4427 hom., cov: 33)
  • Exomes 𝑓: 0.25 (49998 hom.)
• Consequence: GALNS NM_000512.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.65

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 16-88835868-C-T is Benign according to our data. Variant chr16-88835868-C-T is described in ClinVar as [Benign]. Clinvar id is 93181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88835868-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.55 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALNS	NM_000512.5	c.634-19G>A		intron_variant	Intron 6 of 13	ENST00000268695.10	NP_000503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALNS	ENST00000268695.10	c.634-19G>A		intron_variant	Intron 6 of 13	1	NM_000512.5	ENSP00000268695.5

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33257 AN: 152126 Hom.: 4434 Cov.: 33

Gnomad AFR AF: 0.0809

Gnomad AMI AF: 0.385

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.264

Gnomad EAS AF: 0.567

Gnomad SAS AF: 0.277

Gnomad FIN AF: 0.270

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.252

Gnomad OTH AF: 0.262

GnomAD3 exomes AF: 0.271 AC: 67856 AN: 250784 Hom.: 10466 AF XY: 0.272 AC XY: 36913 AN XY: 135632

Gnomad AFR exome AF: 0.0763

Gnomad AMR exome AF: 0.282

Gnomad ASJ exome AF: 0.264

Gnomad EAS exome AF: 0.570

Gnomad SAS exome AF: 0.276

Gnomad FIN exome AF: 0.270

Gnomad NFE exome AF: 0.246

Gnomad OTH exome AF: 0.271

GnomAD4 exome AF: 0.254 AC: 370593 AN: 1461076 Hom.: 49998 Cov.: 43 AF XY: 0.255 AC XY: 185639 AN XY: 726854

Gnomad4 AFR exome AF: 0.0751

Gnomad4 AMR exome AF: 0.282

Gnomad4 ASJ exome AF: 0.265

Gnomad4 EAS exome AF: 0.581

Gnomad4 SAS exome AF: 0.274

Gnomad4 FIN exome AF: 0.269

Gnomad4 NFE exome AF: 0.243

Gnomad4 OTH exome AF: 0.265

GnomAD4 genome AF: 0.218 AC: 33256 AN: 152246 Hom.: 4427 Cov.: 33 AF XY: 0.222 AC XY: 16485 AN XY: 74424

Gnomad4 AFR AF: 0.0809

Gnomad4 AMR AF: 0.242

Gnomad4 ASJ AF: 0.264

Gnomad4 EAS AF: 0.567

Gnomad4 SAS AF: 0.276

Gnomad4 FIN AF: 0.270

Gnomad4 NFE AF: 0.252

Gnomad4 OTH AF: 0.261

Alfa AF: 0.238 Hom.: 877

Bravo AF: 0.214

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Nov 06, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 05, 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.634-19G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 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 0.27 in 276630 control chromosomes in the gnomAD database, including 11195 homozygotes. The observed variant frequency is approximately 130 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. c.634-19G>A has been reported in the literature in individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) in whom other causative variants were identified in homozygous and compound heterozygous states. These data further support a benign outcome due to the presence of this variant in cis with a pathogenic variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 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

- -

Mucopolysaccharidosis, MPS-IV-A Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.17
DANN	Benign	0.37
BranchPoint Hunter		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs12934499; hg19: chr16-88902276;