rs112454391

Positions:

• chr16-88841055-G-A
• chr16-88841055-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000512.5(GALNS):​c.359C>T​(p.Ser120Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000735 in 1,613,256 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0037 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00042 (6 hom.)
• Consequence: GALNS NM_000512.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 4.85

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012253284).
• BP6: Variant 16-88841055-G-A is Benign according to our data. Variant chr16-88841055-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 458621.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00372 (566/152264) while in subpopulation AFR AF= 0.0125 (519/41550). AF 95% confidence interval is 0.0116. There are 3 homozygotes in gnomad4. There are 257 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALNS	NM_000512.5	c.359C>T	p.Ser120Leu	missense_variant	4/14	ENST00000268695.10	NP_000503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALNS	ENST00000268695.10	c.359C>T	p.Ser120Leu	missense_variant	4/14	1	NM_000512.5	ENSP00000268695	P1

Frequencies

GnomAD3 genomes AF: 0.00372 AC: 566 AN: 152146 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00108 AC: 270 AN: 251006 Hom.: 3 AF XY: 0.000743 AC XY: 101 AN XY: 135856

Gnomad AFR exome AF: 0.0129

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.000424 AC: 620 AN: 1460992 Hom.: 6 Cov.: 31 AF XY: 0.000367 AC XY: 267 AN XY: 726810

Gnomad4 AFR exome AF: 0.0132

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000603

Gnomad4 OTH exome AF: 0.000845

GnomAD4 genome AF: 0.00372 AC: 566 AN: 152264 Hom.: 3 Cov.: 33 AF XY: 0.00345 AC XY: 257 AN XY: 74450

Gnomad4 AFR AF: 0.0125

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.000711 Hom.: 1

Bravo AF: 0.00418

ESP6500AA AF: 0.0130 AC: 57

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00125 AC: 152

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mucopolysaccharidosis, MPS-IV-A Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	research	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	Feb 01, 2021	Allele frequency is greater than expected for disorder (BS1_strong) -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	18
DANN	Benign	0.84
DEOGEN2	Pathogenic	0.84	D;.
Eigen	Benign	0.025
Eigen_PC	Benign	-0.073
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D
MetaRNN	Benign	0.012	T;T
MetaSVM	Uncertain	0.026	D
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	0.61	D;N
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Uncertain	0.59
Sift	Benign	0.032	D;D
Sift4G	Benign	0.076	T;.
Polyphen		0.91	P;.
Vest4		0.55
MVP		0.97
MPC		0.25
ClinPred		0.051	T
GERP RS		3.8
Varity_R		0.29
gMVP		0.78

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: rs112454391; hg19: chr16-88907463;