rs1209154325

Variant names:

• chr16-88842711-G-A
• rs1209154325
• NM_000512.5:c.239C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-88842711-G-A
• chr16-88842711-G-C
• chr16-88842711-G-T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000512.5(GALNS):​c.239C>T​(p.Ser80Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,460,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001362798: The most pronounced variant effect results in <10% of normal expression/activity (Tomatsu_2006, Tapiero-Rodriguez_2018).; SCV001547626: "In vitro and vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; low to null in vitro enzymatic activity; PS3_moderate);"; SCV002228773: Experimental studies have shown that this missense change affects GALNS function (PMID:9375852).; SCV005061169: Experimental studies have shown that this missense change affects GALNS function (Tomatsu S, et al., 1997; Tapiero-Rodriguez SM, et al., 2018).; SCV004108330: "In vitro and in vivo studies show that this variant results in significantly reduced enzymatic activity (Tomatsu et al. 1997. PubMed ID: 9375852; Tapiero-Rodriguez et al. 2018. PubMed ID: 29731656)."". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S80W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: GALNS NM_000512.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.79
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• mucopolysaccharidosis type 4A

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001362798: The most pronounced variant effect results in <10% of normal expression/activity (Tomatsu_2006, Tapiero-Rodriguez_2018).; SCV001547626: "In vitro and vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; low to null in vitro enzymatic activity; PS3_moderate);"; SCV002228773: Experimental studies have shown that this missense change affects GALNS function (PMID: 9375852).; SCV005061169: Experimental studies have shown that this missense change affects GALNS function (Tomatsu S, et al., 1997; Tapiero-Rodriguez SM, et al., 2018).; SCV004108330: "In vitro and in vivo studies show that this variant results in significantly reduced enzymatic activity (Tomatsu et al. 1997. PubMed ID: 9375852; Tapiero-Rodriguez et al. 2018. PubMed ID: 29731656)."
• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000512.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 16-88842711-G-A is Pathogenic according to our data. Variant chr16-88842711-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 521930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000512.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALNS	NM_000512.5	MANE Select	c.239C>T	p.Ser80Leu	missense	Exon 2 of 14	NP_000503.1	P34059
	GALNS	NM_001323544.2		c.257C>T	p.Ser86Leu	missense	Exon 3 of 15	NP_001310473.1
	GALNS	NM_001323543.2		c.-311-740C>T		intron	N/A	NP_001310472.1	Q6YL38

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALNS	ENST00000268695.10	TSL:1 MANE Select	c.239C>T	p.Ser80Leu	missense	Exon 2 of 14	ENSP00000268695.5	P34059
	GALNS	ENST00000562593.5	TSL:1	n.2914C>T		non_coding_transcript_exon	Exon 1 of 12
	GALNS	ENST00000565364.1	TSL:1	n.374C>T		non_coding_transcript_exon	Exon 3 of 6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247532 AF XY: 0.00000745

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1460316 Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4 AN XY: 726370

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.0000224 AC: 1 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 85996

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52732

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111632

Other (OTH) AF: 0.0000166 AC: 1 AN: 60350

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Mucopolysaccharidosis, MPS-IV-A (4)
1	-	-	GALNS-related disorder (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Morquio syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		9.8
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.92		Gain of catalytic residue at S80 (P = 0.0047)
MVP		1.0
MPC		0.47
ClinPred		0.95	D
GERP RS		5.0
Varity_R		0.96
gMVP		0.99
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1209154325; hg19: chr16-88909119; COSMIC: COSV99076532; COSMIC: COSV99076532;