chr16-88841948-G-C

Position:

• chr16-88841948-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000512.5(GALNS):​c.268C>G​(p.Arg90Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GALNS NM_000512.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.07

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]

GALNS (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALNS	NM_000512.5	c.268C>G	p.Arg90Gly	missense_variant	3/14	ENST00000268695.10	NP_000503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALNS	ENST00000268695.10	c.268C>G	p.Arg90Gly	missense_variant	3/14	1	NM_000512.5	ENSP00000268695.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mucopolysaccharidosis, MPS-IV-A Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova

Feb 01, 2021

In vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; PS3_supporting); absent from gnomAD v2.1.1 (PM2_moderate); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	29
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.94	D;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.5	D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;.
Polyphen		1.0	D;.
Vest4		0.94
MutPred		0.84		Loss of MoRF binding (P = 0.0219);.;
MVP		1.0
MPC		0.57
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.99
gMVP		0.99

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: chr16-88908356;