rs112454391

Positions:

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

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 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). Synonymous variant affecting the same amino acid position (i.e. S120S) has been classified as Likely benign.

• 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 -11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000512.5
• 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: {Uncertain_significance=1, Benign=1, Likely_benign=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	UniProt
GALNS	NM_000512.5	c.359C>T	p.Ser120Leu	missense_variant	4/14	ENST00000268695.10

Ensembl

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

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) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
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;