16-88835775-G-T

Variant names:

• chr16-88835775-G-T
• NM_000512.5:c.708C>A

Variant summary

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

The NM_000512.5(GALNS):​c.708C>A​(p.His236Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H236H) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GALNS NM_000512.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.355

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 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, 0.993

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALNS	NM_000512.5	c.708C>A	p.His236Gln	missense_variant	Exon 7 of 14	ENST00000268695.10	NP_000503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALNS	ENST00000268695.10	c.708C>A	p.His236Gln	missense_variant	Exon 7 of 14	1	NM_000512.5	ENSP00000268695.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 44

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Benign	1.4
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.26	N
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	4.1	H;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-7.8	D;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;.
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.88		Gain of sheet (P = 0.0266);.;
MVP		0.99
MPC		0.51
ClinPred		1.0	D
GERP RS		-4.9
Varity_R		0.91
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: chr16-88902183;