rs2303271

Positions:

• chr16-88818058-C-T

Variant summary

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

The ENST00000268695.10(GALNS):​c.1431G>A​(p.Glu477=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 1,578,382 control chromosomes in the GnomAD database, including 113,008 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13200 hom., cov: 33)
  • Exomes 𝑓: 0.37 (99808 hom.)
• Consequence: GALNS ENST00000268695.10 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.22

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=-0.65).
• BP6: Variant 16-88818058-C-T is Benign according to our data. Variant chr16-88818058-C-T is described in ClinVar as [Benign]. Clinvar id is 93168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88818058-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.22 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.614 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALNS	NM_000512.5	c.1431G>A	p.Glu477=	synonymous_variant	13/14	ENST00000268695.10	NP_000503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALNS	ENST00000268695.10	c.1431G>A	p.Glu477=	synonymous_variant	13/14	1	NM_000512.5	ENSP00000268695	P1
GALNS	ENST00000562593.5	n.4840G>A		non_coding_transcript_exon_variant	11/12	1
GALNS	ENST00000567525.5	c.*902G>A		3_prime_UTR_variant, NMD_transcript_variant	11/12	2		ENSP00000454484
GALNS	ENST00000568613.5	c.*1394G>A		3_prime_UTR_variant, NMD_transcript_variant	14/15	2		ENSP00000457921

Frequencies

GnomAD3 genomes AF: 0.411 AC: 62462 AN: 151894 Hom.: 13182 Cov.: 33

Gnomad AFR AF: 0.468

Gnomad AMI AF: 0.518

Gnomad AMR AF: 0.410

Gnomad ASJ AF: 0.433

Gnomad EAS AF: 0.633

Gnomad SAS AF: 0.417

Gnomad FIN AF: 0.342

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.441

GnomAD3 exomes AF: 0.407 AC: 81007 AN: 198980 Hom.: 16893 AF XY: 0.404 AC XY: 43499 AN XY: 107702

Gnomad AFR exome AF: 0.477

Gnomad AMR exome AF: 0.410

Gnomad ASJ exome AF: 0.431

Gnomad EAS exome AF: 0.640

Gnomad SAS exome AF: 0.407

Gnomad FIN exome AF: 0.337

Gnomad NFE exome AF: 0.363

Gnomad OTH exome AF: 0.405

GnomAD4 exome AF: 0.370 AC: 527398 AN: 1426368 Hom.: 99808 Cov.: 50 AF XY: 0.371 AC XY: 262620 AN XY: 707422

Gnomad4 AFR exome AF: 0.477

Gnomad4 AMR exome AF: 0.415

Gnomad4 ASJ exome AF: 0.434

Gnomad4 EAS exome AF: 0.625

Gnomad4 SAS exome AF: 0.407

Gnomad4 FIN exome AF: 0.338

Gnomad4 NFE exome AF: 0.351

Gnomad4 OTH exome AF: 0.397

GnomAD4 genome AF: 0.411 AC: 62521 AN: 152014 Hom.: 13200 Cov.: 33 AF XY: 0.412 AC XY: 30590 AN XY: 74294

Gnomad4 AFR AF: 0.468

Gnomad4 AMR AF: 0.410

Gnomad4 ASJ AF: 0.433

Gnomad4 EAS AF: 0.632

Gnomad4 SAS AF: 0.417

Gnomad4 FIN AF: 0.342

Gnomad4 NFE AF: 0.366

Gnomad4 OTH AF: 0.440

Alfa AF: 0.385 Hom.: 3812

Bravo AF: 0.421

Asia WGS AF: 0.478 AC: 1665 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-IV-A Benign:5

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 30, 2017	Variant summary: The GALNS c.1431G>A (p.Glu477Glu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 91177/224468 control chromosomes (882 homozygotes) at a frequency of 0.4061915, which is approximately 199 times the estimated maximal expected allele frequency of a pathogenic GALNS variant (0.0020412), strong evidence that this variant is a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.97
DANN	Benign	0.47

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: rs2303271; hg19: chr16-88884466; COSMIC: COSV51935908;