rs794727625

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr16-88840993-A-T
• chr16-88840993-A-G

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM1 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). ClinVar reports functional evidence for this variant: "SCV000399654: Negligible GALNS activity was observed in leukocytes extracted from one of the patients (Khedhiri et al. 2014).". 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
• Publications: 10 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 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000399654: Negligible GALNS activity was observed in leukocytes extracted from one of the patients (Khedhiri et al. 2014).
• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 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 chr16-88837765-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1048404.
• 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 VariationId is 197149.

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.421T>A	p.Trp141Arg	missense splice_region	Exon 4 of 14	NP_000503.1	P34059
	GALNS	NM_001323544.2		c.439T>A	p.Trp147Arg	missense splice_region	Exon 5 of 15	NP_001310473.1
	GALNS	NM_001323543.2		c.-135T>A		splice_region	Exon 3 of 13	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.421T>A	p.Trp141Arg	missense splice_region	Exon 4 of 14	ENSP00000268695.5	P34059
	GALNS	ENST00000562593.5	TSL:1	n.3830T>A		splice_region non_coding_transcript_exon	Exon 2 of 12
	GALNS	ENST00000565364.1	TSL:1	n.556T>A		splice_region non_coding_transcript_exon	Exon 5 of 6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	1	-	Mucopolysaccharidosis, MPS-IV-A (4)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		9.2
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-13	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	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
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs794727625; hg19: chr16-88907401;