16-88837678-A-G

Variant names:

• chr16-88837678-A-G
• rs3743544
• NM_000512.5:c.510T>C

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.510T>C​(p.Tyr170Tyr) 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 1,613,984 control chromosomes in the GnomAD database, including 1,423 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (150 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1273 hom.)
• Consequence: GALNS NM_000512.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.141

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: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 16-88837678-A-G is Benign according to our data. Variant chr16-88837678-A-G is described in ClinVar as [Benign]. Clinvar id is 93180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88837678-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0773 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALNS	NM_000512.5	c.510T>C	p.Tyr170Tyr	synonymous_variant	Exon 5 of 14	ENST00000268695.10	NP_000503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALNS	ENST00000268695.10	c.510T>C	p.Tyr170Tyr	synonymous_variant	Exon 5 of 14	1	NM_000512.5	ENSP00000268695.5

Frequencies

GnomAD3 genomes AF: 0.0388 AC: 5903 AN: 152114 Hom.: 149 Cov.: 32

Gnomad AFR AF: 0.0318

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.0696

Gnomad ASJ AF: 0.0374

Gnomad EAS AF: 0.0313

Gnomad SAS AF: 0.0840

Gnomad FIN AF: 0.0192

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0357

Gnomad OTH AF: 0.0469

GnomAD3 exomes AF: 0.0457 AC: 11487 AN: 251426 Hom.: 337 AF XY: 0.0473 AC XY: 6432 AN XY: 135910

Gnomad AFR exome AF: 0.0323

Gnomad AMR exome AF: 0.0672

Gnomad ASJ exome AF: 0.0346

Gnomad EAS exome AF: 0.0352

Gnomad SAS exome AF: 0.0800

Gnomad FIN exome AF: 0.0215

Gnomad NFE exome AF: 0.0391

Gnomad OTH exome AF: 0.0451

GnomAD4 exome AF: 0.0383 AC: 55960 AN: 1461752 Hom.: 1273 Cov.: 32 AF XY: 0.0395 AC XY: 28716 AN XY: 727178

Gnomad4 AFR exome AF: 0.0308

Gnomad4 AMR exome AF: 0.0656

Gnomad4 ASJ exome AF: 0.0337

Gnomad4 EAS exome AF: 0.0422

Gnomad4 SAS exome AF: 0.0786

Gnomad4 FIN exome AF: 0.0227

Gnomad4 NFE exome AF: 0.0349

Gnomad4 OTH exome AF: 0.0382

GnomAD4 genome AF: 0.0389 AC: 5917 AN: 152232 Hom.: 150 Cov.: 32 AF XY: 0.0396 AC XY: 2945 AN XY: 74434

Gnomad4 AFR AF: 0.0319

Gnomad4 AMR AF: 0.0700

Gnomad4 ASJ AF: 0.0374

Gnomad4 EAS AF: 0.0306

Gnomad4 SAS AF: 0.0840

Gnomad4 FIN AF: 0.0192

Gnomad4 NFE AF: 0.0357

Gnomad4 OTH AF: 0.0478

Alfa AF: 0.0365 Hom.: 71

Bravo AF: 0.0410

Asia WGS AF: 0.0710 AC: 248 AN: 3478

EpiCase AF: 0.0399

EpiControl AF: 0.0401

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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.510T>C 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 0.046 in 121120 control chromosomes in the ExAC database, including 159 homozygotes. The observed variant frequency is approximately 22-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. Two ClinVar submission 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

- -

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

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Oct 23, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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: 24035930, 9452036) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.98
DANN	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs3743544; hg19: chr16-88904086; COSMIC: COSV51938732; COSMIC: COSV51938732;