rs117053987

Positions:

• chr16-88835760-G-A
• chr16-88835760-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000512.5(GALNS):​c.723C>T​(p.Ala241Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,614,158 control chromosomes in the GnomAD database, including 167 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (9 hom., cov: 33)
  • Exomes 𝑓: 0.013 (158 hom.)
• Consequence: GALNS NM_000512.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.226

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 16-88835760-G-A is Benign according to our data. Variant chr16-88835760-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88835760-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.226 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0082 (1250/152354) while in subpopulation NFE AF= 0.0132 (898/68040). AF 95% confidence interval is 0.0125. There are 9 homozygotes in gnomad4. There are 574 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALNS	NM_000512.5	c.723C>T	p.Ala241Ala	synonymous_variant	7/14	ENST00000268695.10	NP_000503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALNS	ENST00000268695.10	c.723C>T	p.Ala241Ala	synonymous_variant	7/14	1	NM_000512.5	ENSP00000268695.5

Frequencies

GnomAD3 genomes AF: 0.00821 AC: 1250 AN: 152236 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00338

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.00307

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00518

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00725 AC: 1822 AN: 251340 Hom.: 12 AF XY: 0.00712 AC XY: 967 AN XY: 135864

Gnomad AFR exome AF: 0.00265

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00427

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00523

Gnomad NFE exome AF: 0.0132

Gnomad OTH exome AF: 0.00701

GnomAD4 exome AF: 0.0126 AC: 18399 AN: 1461804 Hom.: 158 Cov.: 32 AF XY: 0.0122 AC XY: 8851 AN XY: 727202

Gnomad4 AFR exome AF: 0.00245

Gnomad4 AMR exome AF: 0.00264

Gnomad4 ASJ exome AF: 0.00463

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.00620

Gnomad4 NFE exome AF: 0.0154

Gnomad4 OTH exome AF: 0.00874

GnomAD4 genome AF: 0.00820 AC: 1250 AN: 152354 Hom.: 9 Cov.: 33 AF XY: 0.00770 AC XY: 574 AN XY: 74502

Gnomad4 AFR AF: 0.00337

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00518

Gnomad4 NFE AF: 0.0132

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.0114 Hom.: 4

Bravo AF: 0.00827

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0119

EpiControl AF: 0.0117

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-IV-A Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 16, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	GALNS: BP4, BP7, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 25, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.32
DANN	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs117053987; hg19: chr16-88902168;