16-88814203-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000512.5(GALNS):c.*236C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00771 in 601,032 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0067 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0081 (36 hom.)
• Consequence: GALNS NM_000512.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.663

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-88814203-G-A is Benign according to our data. Variant chr16-88814203-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 321180.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALNS	NM_000512.5	c.*236C>T		3_prime_UTR_variant	14/14	ENST00000268695.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALNS	ENST00000268695.10	c.*236C>T		3_prime_UTR_variant	14/14	1	NM_000512.5	P1
GALNS	ENST00000562593.5	n.5214C>T		non_coding_transcript_exon_variant	12/12	1
GALNS	ENST00000567525.5	c.*1276C>T		3_prime_UTR_variant, NMD_transcript_variant	12/12	2

Frequencies

GnomAD3 genomes AF: 0.00669 AC: 1018 AN: 152100 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0181

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.00479

GnomAD4 exome AF: 0.00805 AC: 3613 AN: 448814 Hom.: 36 Cov.: 4 AF XY: 0.00753 AC XY: 1789 AN XY: 237684

Gnomad4 AFR exome AF: 0.00167

Gnomad4 AMR exome AF: 0.00147

Gnomad4 ASJ exome AF: 0.0127

Gnomad4 EAS exome AF: 0.0000335

Gnomad4 SAS exome AF: 0.0000848

Gnomad4 FIN exome AF: 0.0235

Gnomad4 NFE exome AF: 0.00935

Gnomad4 OTH exome AF: 0.00800

GnomAD4 genome AF: 0.00669 AC: 1018 AN: 152218 Hom.: 5 Cov.: 33 AF XY: 0.00657 AC XY: 489 AN XY: 74418

Gnomad4 AFR AF: 0.00152

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0181

Gnomad4 NFE AF: 0.0101

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00759 Hom.: 0

Bravo AF: 0.00528

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	GALNS: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 14, 2020	See Variant Classification Assertion Criteria. -

Morquio syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Mucopolysaccharidosis, MPS-IV-A Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	1.5
Dann	Benign	0.51

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: rs189375208; hg19: chr16-88880611;