16-88841077-T-C

Variant names:

• chr16-88841077-T-C
• NM_000512.5:c.337A>G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM2 PM5 PP5_Moderate BP4

The NM_000512.5(GALNS):​c.337A>G​(p.Ile113Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,460,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I113F) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: GALNS NM_000512.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.31

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-88841077-T-A is described in Lovd as [Pathogenic].
• PP5: Variant 16-88841077-T-C is Pathogenic according to our data. Variant chr16-88841077-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2724611.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.18603602). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALNS	NM_000512.5	c.337A>G	p.Ile113Val	missense_variant	Exon 4 of 14	ENST00000268695.10	NP_000503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALNS	ENST00000268695.10	c.337A>G	p.Ile113Val	missense_variant	Exon 4 of 14	1	NM_000512.5	ENSP00000268695.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1460846 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726742

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mucopolysaccharidosis, MPS-IV-A Pathogenic:1

Jan 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 113 of the GALNS protein (p.Ile113Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GALNS-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GALNS protein function with a positive predictive value of 95%. This variant disrupts the p.Ile113 amino acid residue in GALNS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7668283, 25137622; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	7.3
DANN	Benign	0.80
DEOGEN2	Uncertain	0.54	D;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.68
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	0.76	N;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.48	N;N
REVEL	Benign	0.24
Sift	Benign	0.32	T;T
Sift4G	Benign	0.20	T;.
Polyphen		0.10	B;.
Vest4		0.46
MutPred		0.57		Gain of phosphorylation at T109 (P = 0.16);.;
MVP		0.65
MPC		0.092
ClinPred		0.40	T
GERP RS		1.1
Varity_R		0.094
gMVP		0.79

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-88907485;