16-88841077-T-C

Variant names:

• chr16-88841077-T-C
• rs118204438
• NM_000512.5:c.337A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PM1 PM2 PM5 PP5_Moderate BP4

The NM_000512.5(GALNS):​c.337A>G​(p.Ile113Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,460,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I113F) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: GALNS NM_000512.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.31
• Publications: 0 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 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 chr16-88841077-T-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 16-88841077-T-C is Pathogenic according to our data. Variant chr16-88841077-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2724611.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.18603602). . Strength limited to SUPPORTING due to the PP5.

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.337A>G	p.Ile113Val	missense	Exon 4 of 14	NP_000503.1	P34059
	GALNS	NM_001323544.2		c.355A>G	p.Ile119Val	missense	Exon 5 of 15	NP_001310473.1
	GALNS	NM_001323543.2		c.-219A>G		5_prime_UTR	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.337A>G	p.Ile113Val	missense	Exon 4 of 14	ENSP00000268695.5	P34059
	GALNS	ENST00000562593.5	TSL:1	n.3746A>G		non_coding_transcript_exon	Exon 2 of 12
	GALNS	ENST00000565364.1	TSL:1	n.472A>G		non_coding_transcript_exon	Exon 5 of 6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1460846 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726742

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52444

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111950

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Mucopolysaccharidosis, MPS-IV-A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	7.3
DANN	Benign	0.80
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.68
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.19	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	0.76	N
PhyloP100		2.3
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.24
Sift	Benign	0.32	T
Sift4G	Benign	0.20	T
Polyphen		0.10	B
Vest4		0.46
MutPred		0.57		Gain of phosphorylation at T109 (P = 0.16)
MVP		0.65
MPC		0.092
ClinPred		0.40	T
GERP RS		1.1
Varity_R		0.094
gMVP		0.79
Mutation Taster		=63/37	polymorphism

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: rs118204438; hg19: chr16-88907485;