16-88813915-C-G

Variant names:

• chr16-88813915-C-G
• rs3759946
• NM_000512.5:c.*524G>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.*524G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.051 in 194,220 control chromosomes in the GnomAD database, including 304 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (248 hom., cov: 33)
  • Exomes 𝑓: 0.047 (56 hom.)
• Consequence: GALNS NM_000512.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.01

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: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 16-88813915-C-G is Benign according to our data. Variant chr16-88813915-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 321174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALNS	NM_000512.5	c.*524G>C		3_prime_UTR_variant	Exon 14 of 14	ENST00000268695.10	NP_000503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALNS	ENST00000268695	c.*524G>C		3_prime_UTR_variant	Exon 14 of 14	1	NM_000512.5	ENSP00000268695.5
GALNS	ENST00000562593.5	n.5502G>C		non_coding_transcript_exon_variant	Exon 12 of 12	1
GALNS	ENST00000567525.5	n.*1564G>C		non_coding_transcript_exon_variant	Exon 12 of 12	2		ENSP00000454484.1
GALNS	ENST00000567525.5	n.*1564G>C		3_prime_UTR_variant	Exon 12 of 12	2		ENSP00000454484.1

Frequencies

GnomAD3 genomes AF: 0.0521 AC: 7930 AN: 152164 Hom.: 247 Cov.: 33

Gnomad AFR AF: 0.0462

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0481

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.0532

Gnomad SAS AF: 0.0746

Gnomad FIN AF: 0.0186

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.0562

Gnomad OTH AF: 0.0599

GnomAD4 exome AF: 0.0470 AC: 1973 AN: 41938 Hom.: 56 Cov.: 0 AF XY: 0.0489 AC XY: 1084 AN XY: 22164

Gnomad4 AFR exome AF: 0.0349

Gnomad4 AMR exome AF: 0.0417

Gnomad4 ASJ exome AF: 0.0967

Gnomad4 EAS exome AF: 0.0403

Gnomad4 SAS exome AF: 0.0673

Gnomad4 FIN exome AF: 0.0139

Gnomad4 NFE exome AF: 0.0440

Gnomad4 OTH exome AF: 0.0473

GnomAD4 genome AF: 0.0521 AC: 7927 AN: 152282 Hom.: 248 Cov.: 33 AF XY: 0.0509 AC XY: 3792 AN XY: 74458

Gnomad4 AFR AF: 0.0461

Gnomad4 AMR AF: 0.0480

Gnomad4 ASJ AF: 0.123

Gnomad4 EAS AF: 0.0530

Gnomad4 SAS AF: 0.0749

Gnomad4 FIN AF: 0.0186

Gnomad4 NFE AF: 0.0562

Gnomad4 OTH AF: 0.0592

Alfa AF: 0.0154 Hom.: 10

Bravo AF: 0.0532

Asia WGS AF: 0.0620 AC: 216 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Adenine phosphoribosyltransferase deficiency Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mucopolysaccharidosis, MPS-IV-A Benign:1

Jan 13, 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. -

Morquio syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.54
DANN	Benign	0.36

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: rs3759946; hg19: chr16-88880323;