NM_000512.5:c.1019G>C

Variant names:

• chr16-88826822-C-G
• NM_000512.5:c.1019G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000512.5(GALNS):​c.1019G>C​(p.Gly340Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G340D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: GALNS NM_000512.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.54

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.

• PM1: In a disulfide_bond (size 111) in uniprot entity GALNS_HUMAN there are 29 pathogenic changes around while only 0 benign (100%) in NM_000512.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-88826822-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALNS	NM_000512.5	c.1019G>C	p.Gly340Ala	missense_variant	Exon 10 of 14	ENST00000268695.10	NP_000503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALNS	ENST00000268695.10	c.1019G>C	p.Gly340Ala	missense_variant	Exon 10 of 14	1	NM_000512.5	ENSP00000268695.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Uncertain	0.79	D
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.046
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	-0.58	N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.47
Sift	Benign	0.40	T
Sift4G	Benign	1.0	T
Polyphen		0.067	B
Vest4		0.43
MutPred		0.52		Loss of catalytic residue at L345 (P = 0.1096);
MVP		0.91
MPC		0.11
ClinPred		0.63	D
GERP RS		5.4
Varity_R		0.75
gMVP		0.85

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: chr16-88893230;