chr16-88813893-G-A

Variant names:

• chr16-88813893-G-A
• rs114447455
• ENST00000562593.5:n.5524C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000562593.5(GALNS):​n.5524C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00371 in 174,342 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0041 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00064 (0 hom.)
• Consequence: GALNS ENST00000562593.5 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.211
• Publications: 0 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00415 (632/152324) while in subpopulation AFR AF = 0.0148 (614/41572). AF 95% confidence interval is 0.0138. There are 3 homozygotes in GnomAd4. There are 289 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALNS	NM_000512.5	c.*546C>T		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	ENST00000562593.5	n.5524C>T		non_coding_transcript_exon_variant	Exon 12 of 12	1
GALNS	ENST00000268695.10	c.*546C>T		3_prime_UTR_variant	Exon 14 of 14	1	NM_000512.5	ENSP00000268695.5
GALNS	ENST00000567525.5	n.*1586C>T		non_coding_transcript_exon_variant	Exon 12 of 12	2		ENSP00000454484.1
GALNS	ENST00000567525.5	n.*1586C>T		3_prime_UTR_variant	Exon 12 of 12	2		ENSP00000454484.1

Frequencies

GnomAD3 genomes AF: 0.00415 AC: 631 AN: 152206 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0148

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000959

GnomAD4 exome AF: 0.000636 AC: 14 AN: 22018 Hom.: 0 Cov.: 0 AF XY: 0.000676 AC XY: 8 AN XY: 11840

African (AFR) AF: 0.0156 AC: 10 AN: 640

American (AMR) AF: 0.000639 AC: 2 AN: 3132

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 324

East Asian (EAS) AF: 0.00 AC: 0 AN: 1652

South Asian (SAS) AF: 0.00 AC: 0 AN: 3338

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 436

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 50

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 11470

Other (OTH) AF: 0.00205 AC: 2 AN: 976

GnomAD4 genome AF: 0.00415 AC: 632 AN: 152324 Hom.: 3 Cov.: 33 AF XY: 0.00388 AC XY: 289 AN XY: 74486

African (AFR) AF: 0.0148 AC: 614 AN: 41572

American (AMR) AF: 0.00105 AC: 16 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.00286 Hom.: 1

Bravo AF: 0.00475

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mucopolysaccharidosis, MPS-IV-A Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 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	1.2
DANN	Benign	0.86
PhyloP100		-0.21
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs114447455; hg19: chr16-88880301;