ENST00000562593.5:n.5014G>A

Variant names:

• chr16-88814403-C-T
• rs11076715
• ENST00000562593.5:n.5014G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000562593.5(GALNS):​n.5014G>A 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 0.26 in 1,549,698 control chromosomes in the GnomAD database, including 55,279 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5101 hom., cov: 33)
  • Exomes 𝑓: 0.26 (50178 hom.)
• Consequence: GALNS ENST00000562593.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.11
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-88814403-C-T is Benign according to our data. Variant chr16-88814403-C-T is described in ClinVar as Benign. ClinVar VariationId is 256330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.534 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALNS	NM_000512.5	c.*36G>A		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	ENST00000268695.10	c.*36G>A		3_prime_UTR_variant	Exon 14 of 14	1	NM_000512.5	ENSP00000268695.5

Frequencies

GnomAD3 genomes AF: 0.244 AC: 37118 AN: 152042 Hom.: 5105 Cov.: 33

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.462

Gnomad AMR AF: 0.265

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.551

Gnomad SAS AF: 0.224

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.287

GnomAD2 exomes AF: 0.281 AC: 44345 AN: 157830 AF XY: 0.279

Gnomad AFR exome AF: 0.143

Gnomad AMR exome AF: 0.294

Gnomad ASJ exome AF: 0.277

Gnomad EAS exome AF: 0.548

Gnomad FIN exome AF: 0.294

Gnomad NFE exome AF: 0.263

Gnomad OTH exome AF: 0.289

GnomAD4 exome AF: 0.262 AC: 366530 AN: 1397538 Hom.: 50178 Cov.: 33 AF XY: 0.262 AC XY: 180345 AN XY: 689434

African (AFR) AF: 0.141 AC: 4466 AN: 31612

American (AMR) AF: 0.296 AC: 10603 AN: 35780

Ashkenazi Jewish (ASJ) AF: 0.276 AC: 6945 AN: 25178

East Asian (EAS) AF: 0.551 AC: 19813 AN: 35926

South Asian (SAS) AF: 0.220 AC: 17444 AN: 79212

European-Finnish (FIN) AF: 0.291 AC: 14194 AN: 48800

Middle Eastern (MID) AF: 0.322 AC: 1431 AN: 4444

European-Non Finnish (NFE) AF: 0.255 AC: 275571 AN: 1078730

Other (OTH) AF: 0.278 AC: 16063 AN: 57856

GnomAD4 genome AF: 0.244 AC: 37128 AN: 152160 Hom.: 5101 Cov.: 33 AF XY: 0.246 AC XY: 18329 AN XY: 74380

African (AFR) AF: 0.143 AC: 5932 AN: 41546

American (AMR) AF: 0.265 AC: 4056 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 960 AN: 3466

East Asian (EAS) AF: 0.551 AC: 2850 AN: 5176

South Asian (SAS) AF: 0.224 AC: 1079 AN: 4820

European-Finnish (FIN) AF: 0.290 AC: 3074 AN: 10582

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.266 AC: 18070 AN: 67982

Other (OTH) AF: 0.286 AC: 604 AN: 2112

Alfa AF: 0.256 Hom.: 1379

Bravo AF: 0.243

Asia WGS AF: 0.328 AC: 1142 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-IV-A Benign:2

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

not provided Benign:2

Apr 12, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Adenine phosphoribosyltransferase deficiency Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Morquio syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.63
DANN	Benign	0.43
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs11076715; hg19: chr16-88880811; COSMIC: COSV51941727; COSMIC: COSV51941727;