chr16-88814072-A-G

Position:

• chr16-88814072-A-G

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.*367T>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 0.334 in 381,070 control chromosomes in the GnomAD database, including 22,336 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (8836 hom., cov: 33)
  • Exomes 𝑓: 0.33 (13500 hom.)
• Consequence: GALNS NM_000512.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.93

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=-0.96).
• BP6: Variant 16-88814072-A-G is Benign according to our data. Variant chr16-88814072-A-G is described in ClinVar as [Benign]. Clinvar id is 321176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.587 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALNS	NM_000512.5	c.*367T>C		3_prime_UTR_variant	14/14	ENST00000268695.10	NP_000503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALNS	ENST00000268695.10	c.*367T>C		3_prime_UTR_variant	14/14	1	NM_000512.5	ENSP00000268695	P1
GALNS	ENST00000562593.5	n.5345T>C		non_coding_transcript_exon_variant	12/12	1
GALNS	ENST00000567525.5	c.*1407T>C		3_prime_UTR_variant, NMD_transcript_variant	12/12	2		ENSP00000454484

Frequencies

GnomAD3 genomes AF: 0.336 AC: 51040 AN: 152022 Hom.: 8827 Cov.: 33

Gnomad AFR AF: 0.325

Gnomad AMI AF: 0.485

Gnomad AMR AF: 0.329

Gnomad ASJ AF: 0.399

Gnomad EAS AF: 0.606

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.308

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.323

Gnomad OTH AF: 0.368

GnomAD4 exome AF: 0.333 AC: 76199 AN: 228928 Hom.: 13500 Cov.: 0 AF XY: 0.332 AC XY: 40592 AN XY: 122408

Gnomad4 AFR exome AF: 0.341

Gnomad4 AMR exome AF: 0.335

Gnomad4 ASJ exome AF: 0.401

Gnomad4 EAS exome AF: 0.596

Gnomad4 SAS exome AF: 0.296

Gnomad4 FIN exome AF: 0.310

Gnomad4 NFE exome AF: 0.317

Gnomad4 OTH exome AF: 0.342

GnomAD4 genome AF: 0.336 AC: 51084 AN: 152142 Hom.: 8836 Cov.: 33 AF XY: 0.337 AC XY: 25037 AN XY: 74366

Gnomad4 AFR AF: 0.326

Gnomad4 AMR AF: 0.329

Gnomad4 ASJ AF: 0.399

Gnomad4 EAS AF: 0.605

Gnomad4 SAS AF: 0.300

Gnomad4 FIN AF: 0.308

Gnomad4 NFE AF: 0.323

Gnomad4 OTH AF: 0.366

Alfa AF: 0.321 Hom.: 9458

Bravo AF: 0.341

Asia WGS AF: 0.406 AC: 1414 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2021	- -

Adenine phosphoribosyltransferase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Mucopolysaccharidosis, MPS-IV-A Benign:1

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 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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.26
DANN	Benign	0.12

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: rs1141390; hg19: chr16-88880480;