rs78127134

chr16-88818027-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000512.5(GALNS):c.1462G>A(p.Val488Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,583,156 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V488V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0020 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (36 hom.)
• Consequence: GALNS NM_000512.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.45

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 -18 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000512.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.009323835).
• BP6: Variant 16-88818027-C-T is Benign according to our data. Variant chr16-88818027-C-T is described in ClinVar as [Benign]. Clinvar id is 194178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88818027-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00204 (311/152326) while in subpopulation EAS AF= 0.0521 (270/5180). AF 95% confidence interval is 0.047. There are 9 homozygotes in gnomad4. There are 182 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALNS	NM_000512.5	c.1462G>A	p.Val488Met	missense_variant	13/14	ENST00000268695.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALNS	ENST00000268695.10	c.1462G>A	p.Val488Met	missense_variant	13/14	1	NM_000512.5	P1
GALNS	ENST00000562593.5	n.4871G>A		non_coding_transcript_exon_variant	11/12	1
GALNS	ENST00000567525.5	c.*933G>A		3_prime_UTR_variant, NMD_transcript_variant	11/12	2
GALNS	ENST00000568613.5	c.*1425G>A		3_prime_UTR_variant, NMD_transcript_variant	14/15	2

Frequencies

GnomAD3 genomes AF: 0.00206 AC: 313 AN: 152208 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0524

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00433 AC: 880 AN: 203200 Hom.: 28 AF XY: 0.00420 AC XY: 464 AN XY: 110368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000654

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0520

Gnomad SAS exome AF: 0.00253

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000109

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00109 AC: 1561 AN: 1430830 Hom.: 36 Cov.: 31 AF XY: 0.00115 AC XY: 814 AN XY: 710208

Gnomad4 AFR exome AF: 0.0000911

Gnomad4 AMR exome AF: 0.0000721

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0269

Gnomad4 SAS exome AF: 0.00305

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000345

Gnomad4 OTH exome AF: 0.00402

GnomAD4 genome AF: 0.00204 AC: 311 AN: 152326 Hom.: 9 Cov.: 33 AF XY: 0.00244 AC XY: 182 AN XY: 74488

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0521

Gnomad4 SAS AF: 0.00539

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.000498 Hom.: 0

Bravo AF: 0.00196

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.00295 AC: 354

Asia WGS AF: 0.0300 AC: 104 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-IV-A Benign:6

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 07, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	curation	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	Feb 01, 2021	Allele frequency is >5% in gnomAD v2.1.1 (BA1_stand-alone); allele frequency is greater than expected for disorder (BS1_strong); multiple lines of computational evidence suggest no impact on gene or gene product (BP4_supporting) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 23, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	16
Dann	Benign	0.97
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.85	L
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.46	N
REVEL	Benign	0.25
Sift	Benign	0.34	T
Sift4G	Benign	0.44	T
Polyphen		0.050	B
Vest4		0.69
MVP		0.95
MPC		0.10
ClinPred		0.016	T
GERP RS		3.1
Varity_R		0.078
gMVP		0.41

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: rs78127134; hg19: chr16-88884435;