rs17603837

Positions:

• chr16-88835869-G-A
• chr16-88835869-G-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.634-20C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0935 in 1,613,416 control chromosomes in the GnomAD database, including 7,807 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 0.091 (695 hom., cov: 33)
  • Exomes 𝑓: 0.094 (7112 hom.)
• Consequence: GALNS NM_000512.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.72

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 place is a probable branch point but likely benign (scored 1 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 16-88835869-G-A is Benign according to our data. Variant chr16-88835869-G-A is described in ClinVar as [Benign]. Clinvar id is 93182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88835869-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALNS	NM_000512.5	c.634-20C>T		intron_variant		ENST00000268695.10	NP_000503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALNS	ENST00000268695.10	c.634-20C>T		intron_variant		1	NM_000512.5	ENSP00000268695	P1

Frequencies

GnomAD3 genomes AF: 0.0905 AC: 13769 AN: 152178 Hom.: 692 Cov.: 33

Gnomad AFR AF: 0.0732

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.0317

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.0418

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.0965

Gnomad OTH AF: 0.107

GnomAD3 exomes AF: 0.0981 AC: 24607 AN: 250874 Hom.: 1414 AF XY: 0.103 AC XY: 13911 AN XY: 135676

Gnomad AFR exome AF: 0.0758

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.158

Gnomad EAS exome AF: 0.0351

Gnomad SAS exome AF: 0.152

Gnomad FIN exome AF: 0.0445

Gnomad NFE exome AF: 0.0997

Gnomad OTH exome AF: 0.106

GnomAD4 exome AF: 0.0938 AC: 137095 AN: 1461120 Hom.: 7112 Cov.: 35 AF XY: 0.0966 AC XY: 70207 AN XY: 726854

Gnomad4 AFR exome AF: 0.0744

Gnomad4 AMR exome AF: 0.106

Gnomad4 ASJ exome AF: 0.159

Gnomad4 EAS exome AF: 0.0418

Gnomad4 SAS exome AF: 0.156

Gnomad4 FIN exome AF: 0.0457

Gnomad4 NFE exome AF: 0.0914

Gnomad4 OTH exome AF: 0.0941

GnomAD4 genome AF: 0.0905 AC: 13787 AN: 152296 Hom.: 695 Cov.: 33 AF XY: 0.0901 AC XY: 6708 AN XY: 74478

Gnomad4 AFR AF: 0.0733

Gnomad4 AMR AF: 0.121

Gnomad4 ASJ AF: 0.156

Gnomad4 EAS AF: 0.0314

Gnomad4 SAS AF: 0.161

Gnomad4 FIN AF: 0.0418

Gnomad4 NFE AF: 0.0965

Gnomad4 OTH AF: 0.108

Alfa AF: 0.0968 Hom.: 203

Bravo AF: 0.0934

Asia WGS AF: 0.0980 AC: 338 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 15, 2019	Variant summary: GALNS c.634-20C>T 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. The variant allele was found at a frequency of 0.096 in 276718 control chromosomes in the gnomAD database, including 1472 homozygotes. The observed variant frequency is approximately 47-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. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Mucopolysaccharidosis, MPS-IV-A Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 23, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.40
DANN	Benign	0.45
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)		0.0		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: rs17603837; hg19: chr16-88902277;