16-88832048-T-C

Position:

• chr16-88832048-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP5_Moderate

The NM_000512.5(GALNS):​c.952A>G​(p.Met318Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M318L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GALNS NM_000512.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.37

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 8 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, 12 uncertain 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 chr16-88832047-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 199031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 16-88832048-T-C is Pathogenic according to our data. Variant chr16-88832048-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 523005.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALNS	NM_000512.5	c.952A>G	p.Met318Val	missense_variant	9/14	ENST00000268695.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALNS	ENST00000268695.10	c.952A>G	p.Met318Val	missense_variant	9/14	1	NM_000512.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mucopolysaccharidosis, MPS-IV-A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Dec 18, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Pathogenic	0.82	D
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.088	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	-1.4	N
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.35
Sift	Benign	0.065	T
Sift4G	Benign	0.10	T
Polyphen		0.0080	B
Vest4		0.42
MutPred		0.48		Loss of loop (P = 0.1242);
MVP		0.96
MPC		0.10
ClinPred		0.90	D
GERP RS		-0.036
Varity_R		0.47
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs537013895; hg19: chr16-88898456;