chr16-88840993-A-T

Variant names:

• chr16-88840993-A-T
• rs794727625
• NM_000512.5:c.421T>A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_000512.5(GALNS):​c.421T>A​(p.Trp141Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W141C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GALNS NM_000512.5 missense, splice_region
• Scores: Splicing: ADA: 0.4005
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 9.21

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 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 16-88840993-A-T is Pathogenic according to our data. Variant chr16-88840993-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197149.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALNS	NM_000512.5	c.421T>A	p.Trp141Arg	missense_variant, splice_region_variant	Exon 4 of 14	ENST00000268695.10	NP_000503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALNS	ENST00000268695.10	c.421T>A	p.Trp141Arg	missense_variant, splice_region_variant	Exon 4 of 14	1	NM_000512.5	ENSP00000268695.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mucopolysaccharidosis, MPS-IV-A Pathogenic:3 Uncertain:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GALNS c.421T>A (p.Trp141Arg) missense variant has been reported in two studies in which it was identified in a homozygous state in two patients with mucopolysaccharidosis type IV, both exhibiting a severe phenotype (Bunge et al. 1997; Khedhiri et al. 2014). The p.Trp141Arg variant was absent from the 116 control chromosomes and is not observed in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium in an area of good sequence coverage, suggesting it is rare. Negligible GALNS activity was observed in leukocytes extracted from one of the patients (Khedhiri et al. 2014). The Trp141 residue is well-conserved. Structural studies of the 3D structure of human GALNS demonstrated that the residue is located in the hydrophobic core of the enzyme near the active site (Rivera-Colón et al. 2012). Based on the available evidence, the p.Trp141Arg variant is classified as likely pathogenic for mucopolysaccharidosis type IV. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Nov 07, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2021

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

In vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; PS3_supporting); the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_supporting); absent from gnomAD v2.1.1 (PM2_moderate); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting) -

Nov 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 141 of the GALNS protein (p.Trp141Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with GALNS-related conditions and/or mucopolysaccharidosis type IVA (PMID: 9298823, 24411403, 33752727, 36964972). ClinVar contains an entry for this variant (Variation ID: 197149). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Feb 05, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D;.
Eigen	Pathogenic	0.84
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-13	D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.99
MutPred		0.96		Gain of disorder (P = 0.0064);.;
MVP		1.0
MPC		0.67
ClinPred		1.0	D
GERP RS		4.8
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
dbscSNV1_ADA	Benign	0.40
dbscSNV1_RF	Benign	0.55
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

LitVar

Other links and lift over

dbSNP: rs794727625; hg19: chr16-88907401;