rs35232749

chr16-88835265-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000512.5(GALNS):c.846C>T(p.Phe282=) 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 1,610,646 control chromosomes in the GnomAD database, including 1,421 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (147 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1274 hom.)
• Consequence: GALNS NM_000512.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0650

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 16-88835265-G-A is Benign according to our data. Variant chr16-88835265-G-A is described in ClinVar as [Benign]. Clinvar id is 93187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88835265-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.065 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0768 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALNS	NM_000512.5	c.846C>T	p.Phe282=	synonymous_variant	8/14	ENST00000268695.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALNS	ENST00000268695.10	c.846C>T	p.Phe282=	synonymous_variant	8/14	1	NM_000512.5	P1

Frequencies

GnomAD3 genomes AF: 0.0390 AC: 5941 AN: 152142 Hom.: 146 Cov.: 32

Gnomad AFR AF: 0.0318

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.0710

Gnomad ASJ AF: 0.0372

Gnomad EAS AF: 0.0304

Gnomad SAS AF: 0.0835

Gnomad FIN AF: 0.0191

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0361

Gnomad OTH AF: 0.0473

GnomAD3 exomes AF: 0.0458 AC: 11223 AN: 245130 Hom.: 320 AF XY: 0.0475 AC XY: 6301 AN XY: 132632

Gnomad AFR exome AF: 0.0311

Gnomad AMR exome AF: 0.0685

Gnomad ASJ exome AF: 0.0343

Gnomad EAS exome AF: 0.0346

Gnomad SAS exome AF: 0.0790

Gnomad FIN exome AF: 0.0212

Gnomad NFE exome AF: 0.0396

Gnomad OTH exome AF: 0.0447

GnomAD4 exome AF: 0.0383 AC: 55806 AN: 1458386 Hom.: 1274 Cov.: 33 AF XY: 0.0395 AC XY: 28617 AN XY: 725128

Gnomad4 AFR exome AF: 0.0306

Gnomad4 AMR exome AF: 0.0669

Gnomad4 ASJ exome AF: 0.0336

Gnomad4 EAS exome AF: 0.0416

Gnomad4 SAS exome AF: 0.0777

Gnomad4 FIN exome AF: 0.0226

Gnomad4 NFE exome AF: 0.0350

Gnomad4 OTH exome AF: 0.0381

GnomAD4 genome AF: 0.0391 AC: 5958 AN: 152260 Hom.: 147 Cov.: 32 AF XY: 0.0398 AC XY: 2964 AN XY: 74448

Gnomad4 AFR AF: 0.0319

Gnomad4 AMR AF: 0.0714

Gnomad4 ASJ AF: 0.0372

Gnomad4 EAS AF: 0.0301

Gnomad4 SAS AF: 0.0836

Gnomad4 FIN AF: 0.0191

Gnomad4 NFE AF: 0.0361

Gnomad4 OTH AF: 0.0482

Alfa AF: 0.0373 Hom.: 67

Bravo AF: 0.0413

Asia WGS AF: 0.0690 AC: 239 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 12, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 15, 2019	Variant summary: GALNS c.846C>T 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 0.062 in 84726 control chromosomes in the gnomAD database, including 143 homozygotes. The observed variant frequency is approximately 30-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. Two 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. -

Mucopolysaccharidosis, MPS-IV-A Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 01, 2018	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	0.67
Dann	Benign	0.58

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: rs35232749; hg19: chr16-88901673; COSMIC: COSV51938722; COSMIC: COSV51938722;