16-88814215-G-C

Position:

• chr16-88814215-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000512.5(GALNS):​c.*224C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00465 in 625,828 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (40 hom., cov: 34)
  • Exomes 𝑓: 0.0019 (16 hom.)
• Consequence: GALNS NM_000512.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.538

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=-0.9).
• BP6: Variant 16-88814215-G-C is Benign according to our data. Variant chr16-88814215-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 321181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0133 (2030/152206) while in subpopulation AFR AF= 0.0461 (1912/41500). AF 95% confidence interval is 0.0444. There are 40 homozygotes in gnomad4. There are 957 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 40 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALNS	NM_000512.5	c.*224C>G		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.*224C>G		3_prime_UTR_variant	14/14	1	NM_000512.5	ENSP00000268695	P1
GALNS	ENST00000562593.5	n.5202C>G		non_coding_transcript_exon_variant	12/12	1
GALNS	ENST00000567525.5	c.*1264C>G		3_prime_UTR_variant, NMD_transcript_variant	12/12	2		ENSP00000454484

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2016 AN: 152088 Hom.: 38 Cov.: 34

Gnomad AFR AF: 0.0459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00596

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00958

GnomAD4 exome AF: 0.00186 AC: 880 AN: 473622 Hom.: 16 Cov.: 5 AF XY: 0.00152 AC XY: 380 AN XY: 250558

Gnomad4 AFR exome AF: 0.0490

Gnomad4 AMR exome AF: 0.00407

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000164

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000699

Gnomad4 OTH exome AF: 0.00411

GnomAD4 genome AF: 0.0133 AC: 2030 AN: 152206 Hom.: 40 Cov.: 34 AF XY: 0.0129 AC XY: 957 AN XY: 74428

Gnomad4 AFR AF: 0.0461

Gnomad4 AMR AF: 0.00595

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00948

Alfa AF: 0.00290 Hom.: 0

Bravo AF: 0.0159

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Adenine phosphoribosyltransferase deficiency Benign:1

Likely 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 13, 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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 24, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.3
DANN	Benign	0.31

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: rs111233947; hg19: chr16-88880623;