rs3743545

Variant names:

• chr16-88837617-A-G
• rs3743545
• NM_000512.5:c.566+5T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000512.5(GALNS):​c.566+5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,612,534 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (46 hom.)
• Consequence: GALNS NM_000512.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001330
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.190
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-88837617-A-G is Benign according to our data. Variant chr16-88837617-A-G is described in CliVar as Benign. Clinvar id is 321203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88837617-A-G is described in CliVar as Benign. Clinvar id is 321203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88837617-A-G is described in CliVar as Benign. Clinvar id is 321203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88837617-A-G is described in CliVar as Benign. Clinvar id is 321203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88837617-A-G is described in CliVar as Benign. Clinvar id is 321203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88837617-A-G is described in CliVar as Benign. Clinvar id is 321203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88837617-A-G is described in CliVar as Benign. Clinvar id is 321203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88837617-A-G is described in CliVar as Benign. Clinvar id is 321203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88837617-A-G is described in CliVar as Benign. Clinvar id is 321203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0506 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALNS	NM_000512.5	c.566+5T>C		splice_region_variant, intron_variant	Intron 5 of 13	ENST00000268695.10	NP_000503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALNS	ENST00000268695.10	c.566+5T>C		splice_region_variant, intron_variant	Intron 5 of 13	1	NM_000512.5	ENSP00000268695.5

Frequencies

GnomAD3 genomes AF: 0.00171 AC: 260 AN: 152082 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0465

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00385 AC: 963 AN: 250434 AF XY: 0.00363

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0505

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00158 AC: 2302 AN: 1460334 Hom.: 46 Cov.: 31 AF XY: 0.00153 AC XY: 1115 AN XY: 726472

African (AFR) AF: 0.0000897 AC: 3 AN: 33442

American (AMR) AF: 0.000112 AC: 5 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0525 AC: 2083 AN: 39692

South Asian (SAS) AF: 0.000429 AC: 37 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52976

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4992

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1111888

Other (OTH) AF: 0.00237 AC: 143 AN: 60286

GnomAD4 genome AF: 0.00170 AC: 259 AN: 152200 Hom.: 6 Cov.: 32 AF XY: 0.00179 AC XY: 133 AN XY: 74402

African (AFR) AF: 0.000193 AC: 8 AN: 41540

American (AMR) AF: 0.000131 AC: 2 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0464 AC: 239 AN: 5154

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67992

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.000461 Hom.: 1

Bravo AF: 0.00237

Asia WGS AF: 0.0160 AC: 55 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-IV-A Benign:3

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. -

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GALNS-related disorder Benign:1

Mar 18, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.28
DANN	Benign	0.61
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000013
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.020		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: rs3743545; hg19: chr16-88904025;